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800-521-0600

Genetie Epidemiology and Phenotypie Resolution ofComplex Traits: Studies in Specifie

Language Impainnent and A1coholism

Mr. Dija Kovac

Department ofBiology

MeGill University~ Montreal

A thesis submitted to the Faeulty ofGraduate Studies and Research in partial fulfillment

of the requirements ofthe degree ofPh.D.

Copyright © Ilija Kavac 2000

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Mojlm roditeljima, Mlrjani i Petru KovaC

To my parents, Mirjana and Petar KovaC

TABLE Of CONTENTS

List ofFigures vii

List ofTables and Appendices viii

Abstraet Xl

Résumé xiii

Preface xv

Acknowledgements xv

Con~butionofAu~oΠ~

Major Contributions to Original Knowledge XIX

Prologue XXI

1. Introduction 1

Rationale and Objectives 1

1.1. Genetic Analysis ofComplex Traits 3

1.1.1. Charaeteristics ofComplex Traits 3

1. 1.2. Major Approaches to Genetic Analysis ofComplex Traits 5

1.1.2.1. Major Methods in Human Statistical Genetics 5

1.1.2.2. Biological Approaches 8

1.2. Phenotype Definition in Genetic Analysis ofComplex Traits 9

1.3. Summary 17

iii

2. Phenotype Dermition iD Specifie Language Impairment (SU) 17

2.1. The Diagnosis and Etiology ofSLI 17

2.2. Potential for Improvement ofPhenotype Definition in SLI 24

2.3. Specific Components ofthe Grammatical Phenotype in SLI 26

2.4. The SLI Phenotype and Attention DeficitIHyperactivity 29

2.5. Summary 34

2(8). Sibling Resemblance for Specifie Components 01Linguistie

Competence in Families 01 Speecb/Language Impaired Cbildren 35

Abstraet 37

Introduction 38

Subjeets and Methods 40

Results 48

Discussion 58

Appendix 64

Bridging Commentary 65

2(b). Attention DefieitlHyperaetivity in SLI Children lDereases Risk of

Speecb/Language Disorden in Fint-Degree Relatives:

A Preliminary Report 66

Abstract 68

iv

Introduction 69

Method 71

Results 7S

Discussion 84

Appendix 89

Commentary 90

3. Phenotype Definition in Alcoholism 92

3.1. The Diagnosis and Etiology ofAlcoholism 92

3.2. Phenotypes in Molecular Genetic Studies ofAlcoholism 9S

3.3. Major Aspects ofPhenotypic Heterogeneity in Alcoholism 97

3.3.1. Early Onset and Late Onset Alcoholism 100

3.3.2. Alcoholism and Antisocial Personality Disorder 106

3.4. Summary 112

3(8). Exploring Phenotypes in Alcobolism: Unrestricted Latent Class Analysis of

Antisocial Behaviors in Alcobol Dependent Males and Females witb Divene

Social AdjustmeDt 113

Abstract IlS

Introduction 117

Subjeets and Methods 119

v

Results 128

Discussion 142

AppendixA 148

AppendixB 149

Bridging ComlDentary ISO

3(b). ExploriDg the Impact of Extended Phenotype in Stratified Samples 158

Copyright Notice IS8

Introduction 1S9 (S211)

Methods 160 (S212)

Results 161 (8213)

Discussion 164 (S216)

4. Final Summary and Conclusions 165

References 178

VI

List ofFigures

Copter %(b).

Attention DefieitIHyperadivity in SU Children lDereases Risk of SpeecbJLanguage

Disorden in Fint-Degree Relatives: A PreliDliDary Report 66

Figure 1. Selection and Subgrouping ofSLI Families 72

Cbapter 3(a).

Exploring Pbenotypes in Aleobolism: Unrestrieted Latent ClaIS Analysis of

Antisocial &ehavion in A1eohol Dependent Males and Females with Divene Social

Adjutment 113

Figure 1. Observed Gender and Symptom Endorsement Probabilities in ASPD Symptom

Based Latent Classes (N = 236, 121 male, 115 female) 130

Figure 2. Observed Gender and Symptom Endorsement Probabilities in CD Symptom

Based Latent Classes (N = 236, 121 male, 115 female) 134

VII

List ofTables and Appendices

ChapterZ.

Phenotype Definition in Specifie Language Impairment (SLI) 17

Table 1. Proportions ofAffeeted First-Degree Relatives in SLI Probands and Control

Subjects 20

Chapter 2(a).

Sibling Resemblance for Specifie Components of Linguistic Competence in F.milies

ofSpeecb/Language Impaired Children 35

Table 1. Language Tests 43

Table 2. Age and Sex Matched Case-Control Comparison ofTest Scores 50

Table 3. Test and Age at Testing Correlations in the English Test Group 52

Table 4. Test and Age at Testing Correlations in the French Test Group 53

Table 5. Sibling Correlations for Specific Components ofLinguistic Competence 55

Table 6. Partial Sibling Correlations Controlling for Age at Testing 57

Appendix. Analyzed Subjects by Test Language and Familial Relationships 64

Chapter 2(b).

Attention DeficitIHyperactivity in SLI Cbildren Increases Risk of SpeecblLanguage

Disorden in Fint-Degree Relatives: A Preliminary Report 66

viii

Table 1. Family History Report for First-Degree Relatives 79

Table 2. Classification ofFirst-Degree Relatives by Family History Report 80

Table 3. Risk by Type ofFirst-Degree Relative 82

Appendix. Family History Questionnaire 89

Chapter 3(a).

Exploring Phenotypes in Alcobolism: Unrestrieted Latent ClaIS Analysis of

ADtisocial Bebavion in Alcobol Dependent Males and Females witb Divene Soeial

Adjustment 113

Table 1. Adult and Childhood Antisocial Behaviors 122

Table 2. Prevalence ofAntisocial Behaviors by Gender 123

Table 3. LCA Model Fitting for ASPD Symptoms in Alcohol Dependent

Males and Females 129

Table 4. LCA Madel Fitting for Conduct Disorder Symptoms in Alcohol Dependent

Males and Females 133

Table 5. Cross-tabulation of ASPD and CD Symptom Based Latent Classes

Stratified by Gender 136

Table 6. Comparison ofLatent Classes Derived from ASPD Symptoms: Alcohol

Dependent Males 137

Table 7. Comparison ofLatent Classes Derived from ASPD Symptoms: Alcohol

Dependent Females 138

Table 8. Psychiatric Co-morbidity in ASPD Symptom Based Latent Classes 141

ix

Appendix A. Symptom Endorsement Probabilities Observed in Latent Classes ofAlcohol

Dependent Individuals Derived ftom Behavioral Symptoms ofASPD

(After 15yr ofAge) 148

Appendix B. Symptom Endorsement Probabilities Observed in Latent Classes ofAlcohol

Dependent Individuals Derived ftom Behavioral Symptoms ofCD

(Before 15yr ofAge) 149

Chapter 3(b).

Exploring the Impact of Extended Phenotype iD Stntified SaDlpies 158

Table 1. Nominally Significant ÙlCi in the Early Subgroup at p < 0.01 162 (S214)

Table 2. Nominally Significant Loci in the Late Subgroup 163 (S215)

Table 3. Allele Sharing in Full Sib Pairs and Sample Sîzes at the ADH3 Functional

Candidate Gene on Chromosome 4 164 (S216)

x

ABSTRACT

Rationale. Definition ofcomplex bebavioral disorders is generally phenomenological in

nature and guided by pragmatic~ rather than genetic, concems. Consequently, important

aspect ofgenetic analysis is the search for novel phenotypic definitions from the

familial/genetic perspective. SU Study 1. SLI denotes an inability to acquire normal

language in the absence ofPeripheral hearing impairmen~ neurological disorder. and

mental retardation. Sibling resemblance for several theoretica11y derived specific

components of the SLI phenotype was examined in families ofSLI children. In 38 sib­

pairs from 10 French-speaking pedigrees, Verb Tense Morphology sulrtests (Real and

Non-real Words) showed nonparametric correlations of0.39 and 0.35, respectl\'el~'

(p<O.05, 2-tailed). In a densely atTccted Anglophone pedigree~ 41 sib-pair showed

familial resemblance with reSPect to Derivational Morphology (F 0.52.. p<O_OI )

SLI Study 2. Family history study in 27 families examined the relationship bet\\'CCn

attention deficit/hyperactivity in SLI children and familial risk ofspeech/language

disorders. Higher odds ofspeech/language disorders were ohserved in first-degree

relatives of 13 SLI children who also had a Medical record ofattention

deficit/hyPeractivity (15/27 vs. 4/46, p=O.OOI). Alcobolism Study 1. Latent class analysis

(LCA) including gender and IS antisocial behaviors (> 15yr) was perfonned in 236

broadly ascenained alcohol.clependent subjects (121 males~ 115 females). Evidence for 3

qualitative behavioral classes was obtained: Socially Adjusted Adults, SAA; Antisocial

xi

Non-Aggressive Adults, ANAA; and Antisocial Agressive Adults, AAA In both

genders, the AAA class had the earliest age ofonset for alcohol dependence (p=O.OO1),

more alcoholic first-degree relatives and more ofother psychopathology. In females, the

ANAA class was intermediate. In the ANAA males, socially adjusted childhood behavior

ditTerentiated the late onset ftom the intermediate onset subgroup. A1coholism Study 2.

Initial sib-pair genome scans were performed in Pedigrees with the pedigree Mean carly

(N=52) and late-onset (N=S3) ofalcoholism from the COGA data set distributed for

GAWIl. Traits ofalcoholism, smoking, and addiction (either alcoholism or smoking)

were examined Subgroups and phenotypes influenced results, the interpretation ofwhich

is a1so discussed in view ofmethodological issues. Conclusion. Complexity ofSLI and

alcoholism is used to derive phenotypes that cao potentially increase the power of

statistical genetic mapping.

XII

RÉsUMÉ

RaisonnelDent. La définition des troubles bébavioraux complexes est généralement de

nature phénoménologique et guidée par des intérêts d'ordre pratique plutôt que

génétique. Par conséquent, la recherche de rlé+1"itions phénotypiques nouvelles dans une

perspective familiale/génétique constitue un aspect important de l'analyse génétique.

Étude SLI no 1. SLI (Specifie Language Impainnent) dénote l'incapacité d'acquérir un

langage nonnal en l'absence d'une atteinte à l'audition périphérique, d'un trouble

neurologique, ou de retard mental. Est examinée la ressemblance entre frères et/ou soeurs

de familles comportant des enfants atteints de SU, en ce qui a trait à un certain nombre

de composantes particuliéres du phénotype Su, dérivées théoriquement. Parmi 38

couples de frères et/ou soeurs chez 10 familles de pedigree francophone, des sous-tests

portant sur la morphologie verbe-temps (mots réels et nOD réels) ont démontré des

corrélations nonparamétriques de 0.39 et 0.35, respectivement (p<O.OS, 2 queues). Chez

un pedigree anglophone densément affecté, 41 couples de frères et/ou soeurs ont

démontré une ressemblance familiale en termes de morphologie dérivationnelle (r=O.52,

p<0.01). Étude SLI no 2. Une étude sur les antécédents familiaux portant sur 27 familles

examine la relation entre le défici de l'attention/hyperactivité chez des enfants atteints de

SLI et le risque, relié à la famille, de développer des troubles du langage. On a observé

une plus grande probabilité de développer des troubles du langage chez les parents de

premier degré de 13 enfants atteints de SLI, qui avaient également des antécédents

xiii

médicaux de déficit de r'attention/hyperactivité (15/27 contre 4/46, p=O.OOI). Étude sur

sujets alcooliques no 1. Une analyse de classe latente incluant le sexe et IS

comportements antisociaux (>lS ans) fut effectuée chez 236 sujets classés comme

alcooliques d'apres des critères généraux (121 hommes, 115 femmes). Des données

sur 3 catégories bébaviorales qualitatives furent obtenues: Adultes Socialement Adaptés

(ASA); Adultes Antisociaux non Agressifs (AANA); et Adultes Antisociaux Agressifs

(MA). Chez les deux sexes, la catégorie MA révélait la manifestation la plus précoce

de déPelldence alcoolique (p=O.OOI), ainsi qu'un plus grand nombre de paents de premier

degré alcooliques et un plus grand nombre de psychopathologies. Chez les femmes, la

catégorie AANA était intermédiaire. Chez les hommes AANA, un comportant

socialement adapté dès l'enfance différenciait le sous-grope au développement tardifde

celui ayant un développement plus précoce. Étude sur sujets alcooliques no 2. Des scans

initiaux de génomes appartenant à des couples frères et/ou soeurs ont été effectués chez

les pedigrees, la moyenne des pedigrees à manifestation d'alcoolisme précoce (N=S2) et

tardive (N=3) de l'ensemble des données COGA étant distribuée pour le GAWII. Les

traits suivants ont été examinés: alcoolisme, tabagisme, et dépendance (soit alcoolisme ou

tabagisme). Les sous-groupes et les phénotypes ont influencé les résultats, don't

l'intepretation fait l'objet d'une discussion portant, en autres, sur des questions de

méthodologie. Conclusion. La complexité du SU et de l'alcoolisme est utilisée pour

dériver des phénotypes pouvant accroître la puissance des statistiques appliquées à la

cartographie de gênes.

xiv

PREFACE

Acknowledgements

The work presented in this thesis is multidisciplinary and was made possible by

contributions ofMany people ofdifferent backgrounds!t too numerous to Imow and

mention aIl in this space. 1have benefited greatly from intellectual exchanges with Dr.

Roberta Palmour, my thesis supervisor. In addition, Dr. Palmour generously agreed to my

pursuit of research that is congruent with my interests, and this is much appreciated.

Other stimulating intellectual contacts, that 1can recall at this time, include Dr. Ken

Mor~ Dr. Clarke Fraser (ret), and also Dr. Guy Rouleau. Particular mention goes to Or.

Chantal Mérette, whose hospitality and cooperativeness introduced me funher to the first­

band research experience. Radha Allard and Berdj Garabedian were very helpful in the

course of consolidating data from various sources in the Genetic Language Impainnent

Project. Finally, during my training Many fellow students ofDr. Palmour made the lab

environment and my experience a positive one.

xv

Contribution ofAuthors

This thesis includes 4 co-authored scientifie manuscripts, submitted to or

published in scientifie joumals. These manuscripts, copyrights where applicable~ and

contnbutions of individual co-authors are listed below. Ali manuscripts were also co­

authored by my thesis supervisor, Dr. Roberta Palmour.

Chapter 2(a)

'~Sibling Resemblance for Specifie Components ofLinguistic Competence in Families of

SpeechlLanguage Impaired Children"; co-authored with Or. Myrna Gopnik, and

submitted to the Journal ofNeurolinguistics.

1have designed and implemented data analysis, and interpreted results. Dr Myrna

Gopnik, Dept. Linguistics, was the Principal Investigator in the McGill Genetic Language

Impainnent Project (GLIP). Dr. Gopnik designed the criteria according to which her

research group selected families for language testing in the GLIP projeet. Dr. Gopnik also

designed the language test instrument and supervised aetual testing, which was performed

by her linguistic research group.

XVI

Chapter 2(b)

«Attention DeficitIHyperactivitt in SU Children Increases Risk ofSpeechlLanguage

Disorders in First-Degree Relatives: A Preliminary Report"; co-authored with Berdj

Garabedian and Cbristele Du Souich, and submiued to the Journal ofCommunication

Disorders.

1have designed and implemented inclusion/exclusion criteria for specific

language impainnent (SLI) in this particular study, data analysis, and interpreted results.

Berdj Garabedian examined original Medical records, mostly in French language, and

prepared summarized Medical record information that was used in this study. Christele du

Souich condueted family history telephone interviews.

Chapter 3(a)

~'Exploring Phenotypes in Alcoholism: Unrestrieted Latent Class Analysis ofAntisocial

Behaviors in Alcohol Dependent Males and Females with Diverse Social Adjustment";

co-authored with Dr. Chantal Merette, Mireille Cayer, Lucie Legault, and Dr. Maurice

Dongier, and submitted to Alcoholism: Clinical and Experimental Research.

1have designed and implemented data analysis, and interpreted results. Dr

Chantal Merette reviewed statistical analyses, provided useful input on presentation of

results and, with the help ofMireille Cayer, independently repeated presented statistical

analyses. Dr Merette also POinted out a statistical issue in the analysis of the relationship

between childhood and adult latent classes, which 1corrected. Or. Maurice Dongier and

Lucie Legault actively participated in the recruitment ofsubjects, data collection and

xvii

•

preparatio~ within the Montreal centre ofthe International WHOIISBRA Study ofState

and Trait Markers ofAlcoholism.

Chapter 3(b)

"Exploring the Impact ofExtended Phenotype in Stratified Samples"; ~authored with

Eric Rouillard and Dr. Chantal Merette. This manuscript is published in Genetie

Epidemiology 17(Suppll), S211-S216 (1999). Copyright@ Wiley-Liss, Inc. The

Collaborative Group for Research 00 Genetics ofAlcoholism (COGA) distnbuted the

analyzed data set to participants ofthe Genetic Analysis Workshop Il held in Arcachon,

France, 1998, where a part ofthis study was presented as a poster.

1have designed and implemented data analysis, and interpreted results. Eric

Rouillard provided helpful advice in mastering teehnical aspects ofcomputer-based

linkage analysis. Dr. Merette provided her expertise in examinatioo of my study proposaI,

and generaI supervision ofstatistical analyses.

xviii

•

Major Contributions to Original Knowledge

Cbapter 2(a)

Included manuscript, in submissioD, examined sibling resemblance for various

theoretically derived specifie components oflinguistie competence in anglophone or

francophone families ofSLI children. Among these varied components, Verbal Tense

Morphology and Derivational Morphology showed greatest sibling resemblance. These

phenotypic components May therefore he ofpartieular interest for further familiaVgenetic

studies.

Chapter 2(b)

Included !!!a!l'lSCrip~ in submission, provides preliminary evidence of increased

risk ofspeechllanguage disorders in first-degree relatives ofSLI children who also have

attention deficit and/or hyperactivity behavioral problems. In addition, the evidence

Persists when relatives with leaminglreading disorders, often associated with

speech/language disorders, are counted as unaffected, making for a more robust result.

These findings merit further investigation ofthe relationship between SLI and attention

deficitlhyperactivity, which is ofpotential interest for genetic studies in SLI.

xix

Chapter 3(a)

Ineluded manuscript, in submission, provides evidence for qualitative

differentiation ofalcohol dependent individuals with respect to patterns ofspecifie

antisocial bebaviors, rather than continuous variation along the single dimension of

"severity". This result is ofpotential interest for genetic mapping studies, which are

currently focused on less precisely defined antisocial alcoholism.

Cbapter 3(b)

Included manuscript, published in a scientific journal, explores the impact of

phenotype-based stratification in statistical genetic analysis ofalcoholism as a complex

trait (an initial genome scan), and provides opportunity to compare results with

statistically identical analysis ofthe same, but unstratified, data set reported by original

investigators. In addition, potential impact ofphenotype definition that encompasses

alcoholism and/or smoking, a genetically correlated trait, is explored The results suggest

that, under certain conditions, these phenotype-based approaches may he heneficial for

identification of some genetic risk factors in complex traits.

xx

PROLOGUE

The ingenious discovery of laws according ta which genes, unobserved at the

time, are transmitted from parents ta otIspring was possible only because Gregor Mendel,

unknowingly, studied a particular class ofphenotypes. These phenotypes were

determined entirely by the information content ofthe DNA sequence al single genetic

loci, regardless ofthe variable ontogenetic context ofother genetic and environmental

factors. Not surprisingly, developmentaI biologists were among the first to articulate an

organismic perspective, which recognizes that biological organisms belong to the more

general class ofself-organizing systems, characterized by the emergence ofnovel

properties from interactions ofmultiple system elements (Von Bertalanffy, 1933, and

references therein). Likewise, experimental geneticists have long known that the

Mendelian concept ofthe phenotype applies only ta some and not a1l phenotypes

(Dobzhansky, 1937). During the past two decades, the organismic view ofthe path from

genes to phenotypes and a public sense ofurgency have forcefully converged ooto

genetics ofdevelopmental bebavioral disorders.

XXI

1. INTRODUCTION

RATIONALE AND OBJECTIVES

Rationale

The genetic basis ofMany disorders showing Mendelian inheritance has bccn

identified in the past decades. Complex disorders by definition do not show Mendehan

inheritance, and require more elaborate approaches to genetic analysis. In panlcular.

phenomenological clinical diagnoses ofcomplex behavioral disorders are poorly sUltcd

for genetic studies. The derivation ofnovel, more homogenous phenotypes. from the

familiaVgenetic perspective holds the potential to improve the power for statlstlcal

identification ofgenetic risk factors. In this work, we focus upon two eomplex bcha\'loral

disorders [specifie language impairment (SLD and alcoholism], ta which these

generalizations apply.

Objectives

1. To examine which ofa variety ofdifferent, theoretically derived components ofthe

SLI phenotype May show the greatest sibling resemblance.

1

2. To examine whether the risk ofspeecb/language disorder in first-degree relatives is

greater in 811 children who also bave attention deficitlhyperaetivity bebavioral

problems.

3. To examine whether subgroups ofalcohol-dependent individuals \vith distinctive

patterns ofspecific antisocial behaviors cao he empirically defined using a

multivariate statistical approach.

4. To examine the impact ofstratification inta the early and late-onset subgroups on the

results from the initial genome scan ofalcohol dependence, performed on the COGA

data set from the Genetic Analysis Workshop Il.

Details ofthe background pertinent to the aixl";e rationale and objectives are

presented further in this chapter.

2

1.1. GENETIC ANALYSIS OF COMPLEX 1RAITS

1.1.1.Cbaracteristics ofComplex Traits

In the field ofgenetics, the term "complex trait" is commonly taken to denote any

trait that does not show simple mendelian inheritance. Following are sorne characteristic

ofsuch traits:

• No specifie genetie allele is either neeessary nor sufficient

• Common genetie aileles with low penetrance

• Genetic locus and/or allelic heterogeneity

• Pleiotropy (a gene influences multiple traits)

• Multiple genes (locus heterogeneity, additive, threshol<L inter-genic interactions or

epistasis)

• Environmental effeets

• Gene(s) x environment(s) interactions

• SPecial modes ofinheritance (imprinting, dynamic mutations, mitochondrial genes)

• Phenocopies

• Ambiguous boundaries of phenotype definition

In principle, a complex trait can show any combination, or ail ofthe above

complexities. An important premise that allows for the 44rule of thumbn inferences of

relative trait complexity is that the traits at the higher hierarchicallevel ofdevelopmental

3

•

•

organization are directIy influenced by a larger number ofgenetie and environmental

factors, and are therefore expected to he etiologically more complex (Sehork, 1997).

Accordingly, behavioral traits are expected to he the most complex because the greatest

proportion ofgenes per organ are expressed in the brain, roughly estimated at -30.000

(NINDS, 1990; SutclitTe, 1988), and their highly concerted action is constantly

influenced by interactions with the environment (Eisenberg, 1995). In agreement with

this expeetation, psychiatrie disorders are especially notorious for ambiguous boundaries

ofphenotype definition and. failure to replieate findings ofgenetic vulnerability lOCI

(Craddoek & Jones, 1999; De Lisi, 2000; Kidd, 1997; Portin & Alanen, 1997. Runer et

al. 1999).

The foundations ofcurrent, widely used DSM-IV (APA, 1994) c1assifieatlon ln

psychopathology, as weIl as problems and approaches, are reviewed in Nathan and

Langenbucher (1999). Nosologieal problems include unknown etiology9 comorbldlty and

unclear boundaries between disorders; diagnostic validity; diagnostic stability o\'er ume:

and diagnostic reliability (partieularly for schizophrenie speetrurn disorders. personahty

disorders, and sorne childhood and adolescent disorders). Andreassen (1995) proposed a

"gold" standard for validation that ineludes laboratory tests derived from

multidisciplinary approaches, in addition to traditional approaches such as cl mlcal

description and family studies; these new approaches would "link a psychiatnc dlagnosis

to its underlying abnormalities in DNAn. The latter, however, may be an overly

reductionistic statement, unlikely to hold given the ineffieiency ofaccumulated genetic

analyses which have otherwise successfully revealed DNA abnormalities in many

relatively simple disorders. Because many behavioral disorders arise from complex

4

developmental processes spanning several hierarchicallevels oforganization above the

DNA sequence, common functional genetic polymorphisms, rather than traditional rare

mutant alleles, may act as risk factors that put individuals on the probabilistic

developmental path towards a psychiatric diagnosis (Rutter et al. 1999). In agreement

with Andreassen7 s recommendation, contemporary efforts emphasize the search for

neurobiological and genetie-familial validators that eould inform etiology and treatment

ofbehavioral disorders, although perhaps in a more complex manner than traditionally

envisaged. Approaehes to identification ofgenetically relevant phenotypes, which often

do not correspond to phenomenological diagnostic categories, are outlined further in this

chapter.

1.1.2. Major Approaehes to Genetic Analysis ofComplex Traits

In this briefoverview, major methodological approaches will be provisionally

grouped on the basis of predominantly statistical versus predominantly biological

perspectives, although these arbitrary groups are necessarily more or less related.

1. 1.2.1.Major Methods in Human Statistical Genetics

Linkage Analyses

Following the notion that human DNA polymorphisms can he used as markers for

closely linked genes (Botstein et al. 1980), the genes which cause many rare Mendelian

human diseases were identified, using the classical LOD score method of linkage analysis

5

•

in large pedigrees or sets ofpedigrees (Antonarakis &. McKusick, 2000). The power of

this method depends on the correct specification ofthe genetic model of inheritance,

which usually cannot he determined in complex traits (Risch, 1992). The development of

more robust, non-parametric (genetic model-Cree) linkage methods that use only affected

pairs ofrelatives circumvented this problem (Haseman &. Eiston, 1972; Kong and Cox,

1997; Kruglyak et al. 1996; Weeks & Lange, 1988; Weeks &, Lathrop~ 1995). The basic

assumption is that, if the genetic locus is etiologically important, pairs ofatTected

relatives will share alleles in that region to a greater extent than is expected by chance.

While this strategy is less powerful than the classical LOD score analysis with the

correctly specified model, it is more robust to etiological complexity (Lander &, Schork,

1994). It is therefore frequendy applied to genetic analysis ofcomplex traits, in particular

using affected sib-pairs (Field &, Tobias, 1997; Lander &. Schork, 1994; Ott, 1999;

Tomlinson &, Bodmer, 1995; Weeks &, Lathrop, 1995).

Association Studies

Traditionai association studies compare the frequency ofaileles or genotypes

among affected individuals (cases) with those found in unaffected individuals (controls).

Particular care in case~ontrol association studies needs to he taken to avoid factors that

could cause spurious positive or negative results, such as inappropriate choice ofcontrois

which can introduce population admixture (Commings, 1998). A useful strategy in this

respect is the transmission disequilibrium test or TOT, which detects linkage as weil

(reviewed in Spielman &, Ewens, 1996). The TOT is based on the premise that a parent

heterozygous for a trait-associated ailele should more often transmit that particular aIlele

6

to an atTected child The control group is not required in TDT analysis because the

untransmitted allele is used as a controL It is argued tbat association studies are more

powerful for identification ofgenes with small effects than linkage studies, making them

suitable for detection ofvulnerability genes in complex disorders (Comings, 1998; Risch

& Merikangas, 1996).

Some Issues in Statistical Significance

Statisticallinkage analyses ofmany marker loci across the genome (genome

scans) are frequently conducted in genetic analysis ofcomplex traits. An obvious

advantage ofthis approach is coverage ofthe genome. However, multiple tests at

individual marker loci pose a particular problem with respect to statistical interpretation

of results. There are differences in opinion regarding the appropriate correction ofthe

significance criteria (Ott, 1999), with sorne authors providing statistical guidelines based

on simulation studies and others preferring judicial reporting ofuncorrected p-values

(Curtis, 1995; Lander & Kruglyak, 1995; Witte et al. 1995). In principle, empirical p­

values for any study can be obtained by computer simulation under the assumption ofno

linkage, for example Brzustowicz et al. (1997) determined empirical p-values to account

for testing ofmultiple markers and multiple phenotypes in a genome scan of

schizophrenia. Other authors do not correct for multiple phenotypes, e.g. Fisher et al.

(1999) in a study ofdyslexia. Regardless of the initial p-value, the standard for declaring

statistical genetic linkage is independent replication (Lander & Kruglyak, 1995), which

however becomes progressively more difficult with the increased dependence of the

genetic locus effect on the unobserved variability among atTected individuals. The latter

7

MaY in part account for frequent non-replication oflinkage results in psychiatrie disorders

(De Lisi, 2000). Beyond statistical evidence, the 'gold" standard for declaring a gene

etiologically relevant also requires a demonstration of funetional influence on the disease

phenotype; c.g., the Apo E4 allele ofthe Apo E gene, encoding a protein that binds to P­

amyloid, is one ofetiological factors in Alzheimer's disease (reviewed in Rubînsztein.,

1997).

Other Statistical Methods

In addition to the frequently used methods notOO above, there are alternatives, e.g.

models based on variance components (Amos et al. 1994; Schork, 1993; Blangero &

Almasy, 1997). A novel method based on pattern recognition in neural networks detects

contribution of individualloci as a deviation from the Mean contribution ofail marker

loci in the genome (Lucek &~ 1997). For a comprehensive overview ofstatistical and

other methods and problems in human genetic analysis, the reader is referred to Ott,

1999.

1.1.2.2. Biological Approaches

[n human genetic analysis, it cao he advantageous to use isolated populations

which may be genetically and environmentally more homogenous due to their

evolutionary history (Jorde, 1995). Moreover, animal models including various

inbreeding techniques offer experimental advantages to identifying quantitative trait loci

(QTL), each ofwhich accounts for sorne small percent ofthe variance in complex

8

disorders (Lander & Schork, 1994). The extent ta which results ftom animal studies are

relevant to humans depends on the evolutionary conservation ofthe gene and gene

fonction, and is somewbat more limited in psychiatrie disorders because corresponding

end-point phenotypes cannot readily be diagnosed in animais (Flint & Corley, 1996).

However, functional studies in humans or animais can identify a priori candidate genes

relevant to the trait in question (Hill, 1998; Lander & Schork, 1994). One problem in the

candidate gene approach to complex behavioral disorders is the large number ofpotential

candidate genes expressed in the brain, an organ characterized by highly inter-related

functional processes.

1.2. PHENOTYPIC DEFINITION IN GENETIC ANALYSIS

OF COMPLEX TRAITS

Ali ofthe statistical methods for the identification ofgenes predisposing to

complex traits lose more or less power when the effects ofvulnerability loci are sensitive

to unobserved variability among afIected individuals, so that these loci are neither

necessary nor sufficient for the expression ofthe phenotype. It is therefore important to

ineorporate additional information pertaining to tbis unobserved variability ioto the

design ofgenetic mapping studies, in order to improve the power for detection ofspecifie

genetic effeets. In addition to previously noted approaches based on multilocus methods,

special more homogenous populations, or animal inbred strains, an important strategy in

this respect is the derivation ofmore homogenous phenotype definitions (Lander &

Sehor~ 1994; Ott & Bbat, 1999; Schor~ (997). Major approaches to the definition of

9

more homogenous phenotypes can he heuristically outlined onder the themes ofclinical

characteristics, severity~ developmental chronology, family history, comorbidity, specifie

associated traits or specifie components ofthe diagnostic phenotype, and the use of

multivariate statistically derived phenotypes.

Clinical Characteristics

Many complex disorders have variable clinical characteristics that can he used to

identify more homogenous phenotypes. In the example ofdiabetes, genetie analyses of

Type 1or insulin-dependent diabetes mellitus (IDDM) identified multiple susceptibility

loci in mice and humans (reviewed in Field & Tobias, 1997; Todd, 1999). The Type 2 or

non-insulin dependent diabetes mellitus (NIDDM) is both clinically and genetically

distinct from the Type 1 diabetes (permutt et al. 1998). Neurofibromatosis Type 1 is

linked to chromosome 17 (Goldgar et al. 1989), while clinically distinct

neurofibromatosis Type 2 is Iinked to chromosome 22 (Rouleau et al. 1993). Sometimes,

as in autosomal dominant cerebellar ataxias, clinical heterogeneity is extensive even

within famiIies, 50 that disease classification requires knowledge of the underlying

genetic locus, several of which were identified in different families (reviewed in Muller

& Graeber, 1996).

Severity

For traits measured directly on the continuous scale, i.e. hypertensio~ it is

obvious that individuals at the extreme ofthe affected phenotype can he considered more

severely affected. An example ofgene mapping using this strategy is linkage ofthe

10

angiotensin gene to essential hypertension (Jeunemaitre et al. 1992). A population based

and a clinically ascertained sample were studied. In the population based sample, linkage

was observed only in the subset ofextremely hypertensive subjects, while in the clinical,

more severely affected sample, linkage was observed in the total sample. When extremely

hypertensive subjeets from both samples were pooled, the evidence for linkage was

further improved. The angiotensin gene remains a strong candidate gene for essential

hypertension, not considering rare mendelian syndromes for which single gene mutations

are shown to increase blood pressure (Dominiczak et al. 2000). In other comple" traits,

quantitative measures ofseverity cao be constructed. For example, a recent linkage study

ofschizophrenia utilized a number ofphenotypes: categorical definitions of

schizophrenia, positive-symptom (psychotic), negative-symptom (deficit) and general

psychopathology-symptom scales as quantitative traits (Brzustowicz et al. 1997).

Significant genetie linkage to chromosome 6 was observed only for the positive-

symptom..score phenotype that was interpreted as the measure ofseverity for these

symptoms. Clinical observations can also he interpreted in the conteX! ofseverity. For

eKalllple, Kendler et al. (2000) reported that affected individuals from families in which

schizophrenia was linked to chromosome 8p had significantly more affective

deterioration, poorer outcome, and more thought disorder.

Developmental Chronology

It is known that the expression ofmany genes is dependent on the stage of

development, including those expressed in the brain (e.g. Tice et al. 1996). Accordingly,

the effects ofdifferent genes predisposing to complex disorders may he expressed at

Il

different stages ofdevelopment. Consequently, the age ofonset ofcomplex disorders can

he useful for the identification ofmore homogenous phenotypes. In familial Alzheimer

disease (AD), which accounts for ....5% ofail AD cases, difTerent genetic loci are mapped

to the early onset and Jate onset AD, otherwise neuropathoJogically indistinguishable

phenotypes (reviewed in: RubinszteiD., 1997; Shastry &, Giblin, 1999). The research in

early anset forms ofbreast cancer allowed identification ofvulnerability genes (Hall et al.

1990; Sellers, 1997; Wooster et al. 1995). In diabetes, genetic mutations were identified

in the analyses ofthe maturity onset diabetes in the young (MOOY) phenotype

(Yamagata et al. 1996).

Family Historv

The requirement for multiple affected relatives is a common method of

identifying families that are more likely ta segregate susceptibility genes in complex traits

(Lander & Schork, 1994; Hill, 1998), because sporadic cases are considered less likely to

have a substantial genetic component. This approach may not he always optimal as the

power ofspecifie pedigree structures can vary dramatically among models producing

identical population prevalence and sibling recurrence rate, while random ascertainment

typically involves a modest loss ofpower (McCarthy et al. (998).

Comorbidity

Comorbidity denotes co-occurrence ofdisorders in the same individual. At the

population level, co-occurrence ofbehavioral disorders above the frequency expected by

chance is often encountered. Comorbidity has notable adverse physical, psychological

12

•

and social consequences, prompting substantial research ïnterest. Several recent reports

review findings and approaches to comorbidity in the field ofpsyehopathology (Angold et

al. 1999; Clark et al. 1995; Klein &. Riso, 1993; Nathan &. Langenbucher, 1999; Sher &,

Trull, 1996), where substance related disorders, personality disorders, depression and

anxiety show highest levels ofcomorbidity. In an influential report, Klein and Riso

(1993) outlined Il pltential causes ofcomorbidity, Many ofthose methodological

artifacts, and suggested approaches to distinguishing these models, developed further by

Neale and Kendler (1995). With familial data, sorne models ofcomorbidity can he

resolved by examining risks to relatives ofprobands with and without comorbid disorder,

e.g. Biederman et al. (1992), or by a multivariate pedigree analysis, e.g. Stallings et al.

e1997). A powerful approach to study ofcomorbidity is multivariate analysis of twin data,

whieh can disentangle relative contnbutions ofgenetic and environmental factors to

disorder speeific and comorbid variation (Kendier et al. 1987; Kendler et al. 1995;

Slutske et al. 1998). For example, Kendler et al. (1995) reported that, in female twins,

genetic influences on phobia, generalized anxiety disorder, Pallie disorder, bulimia, major

depression and alcoholism are neither highly disorder specifie (except for alcoholism) nor

highly nonspecific. Patterns ofpsychiatrie symptoms, rather than diagnostic categories,

can also be analyzed in this manner; Kendler et al. (1987) reported that genetie influences

on symptoms ofdepression and anxiety aet in a largely non-specifie way on the overall

level ofsymptoms, while some environmental factors showed a more disorder-specific

influence.

In genetic mapping studies, comorbidity could he exploited by requirement for

dual diagnosis in affeeted individuals, for example in alcoholism with antisocial

13

personality disorder (Lappalainen et al. 1998). The association ofalcoholism and

antisocial personality disorder, for which there is evidence ofcommon genetic factors, is

presented in more detail in the Chapter 3. Another approach may he to use severa!

phenotype definitions that eneompass increasing number ofdiagnostic categories, some

ofwhich May represent diagnostic sub-threshold syndromes for the disorder of interest.

Forexample, Straub and coworkers (1995) used 4 increasingly broad phenotype

definitions in the study ofschizopbrenia. These definitions were: narrow - schizophrenia,

poor outcome schizophrenie affective disorder, and simple schizophrenia; intennediate­

narrow plus schizotypal personality disorder, and non·affective psychotic disorders; broad

- intermediate plus pgychotic affective illness, paranoid, avoidan~ and schizoid

personality disorder; and ail psychiatric diagnoses. Evidence for linkage to chromosome 6

was maximal using intennediate phenotypic definition and decreased when this definition

was either narrowed or broadened.

Specifie Associated Traits and Soecifie Components of the Diagnostic Phenotype

Specifie traits that are associated with complex disorders, as weil as specifie

symptoms, are potentially useful in mapping ofgenetic loci with specifie etfects. This

strategy May be particularly important for disorders that are most complex, i.e. behavioral

disorders. An example ofthe associated trait May he the decrease in normal inhibition of

the P50 auditory evoked response to the second ofpaired stimuli, which is associated

with attention disturbances in sehizophrenia, and oceurs also among non-schizophrenie

relatives in a distribution consistent with inherited vulnerability ta the illness (Freedman

14

et al. 1997). These authors reported linkage ofthis neurophysiological phenotype to

chromosome 15 at the site ofthe a7-nicotinic receptor gene.

Analysis ofsPeCific theoretically derived components ofthe diagnostic phenotype

is the current approach ofchoice for genetic analysis ofdyslexia or specific reading

disability (Fisher et al. 1999; Gayan et al. 1999; Grigorenko et al. 1997). Reading

Performance, the principal impairment in dyslexia, can he decomPOsed into several

component processes including word recognition, orthographic coding, phonological

decodin& and phonological awareness (Gayan et al. 1999). Severallinkage studies of the

chromosome 6p region found evidence ofvarYing strength for sPecifie phenotYPlc

components; strongest evidence was found for phonological and orthographie skills. and

weaker evidence was obtained for word recognition or single word reading (Fisher et al.

1999; Gayan et al. 1999; Grigorenko et al. 1997). Phonological and orthographie

processing are individually heritable, with behavioral genetic evidence for bath eommon

and independent genetic factors (Oison et al. 1994). Above noted linkage evidencc

suggests that common genetic factors rnight include a locus on chromosomc 6p

Ultimately, genetic analysis might identify genes with comPOnent-specifie efTect.

although such a conclusion requires elimination ofmethodological explanatlons. sueh as

differences in accuracy ofassessment ofdifferent phenotypes, or marker informat1\'cness

(pennington, 1997).

Multivariate Phenotype Definitions

Novel phenotype definitions for genetic mapping studies can he obtained using

some ofnumerous formai multivariate statistical methods, i.e. factor analysis, principal

IS

component analysis, etc., to combine information trom multiple variables in a composite

phenotype. This cm he advantageous because it uses information from multiple data

items typically collected in studies ofpoorly defined complex phenotypes (McCIeam,

1993), and because it circumvents prohibitively expensive corrections for multiple

comparisons with univariate analyses ofManY variables (Ott and Rabinowitz, 1998).

Common criteria for a priori selection ofthe useful multivariate phenotype are increased

heritability (Grove, 1994; McClearn, 1993; Ott and Rabinowitz, 1999), or the best fit to a

major gene transmission (Goldin et al. 1980; Zlotnik et al. 1983), a1though these criteria

might not he optimal for mapping ofail loci (Allisson et al. 1998). An example for the

use ofa priori defined multivariate phenotype in linkage analysis ofa complex trait is a

genome scan ofa1coholism phenotype (Foroud et al. 1998), derived from the latent class

analysis (categorical analog offactor analysis) ofsymptoms ofa1coholism. Sorne

statistical methods combine information from multiple phenotypes in the course of

linkage analysis to improve power (reviewed in Allison et al. 1998).

1.3. SUMMARY

Increasing phenotypic information from the familial/genetic perspective is an

important approach to genetic dissection ofcomplex traits.

16

2. PHENOTYPE DEFINITION

IN SPECIFIC LANGUAGE IMPAIRMENT (SLI)

2.1. nIE DIAGNOSIS AND ETIOLOGY OF SLI

Diagnosis of SLI

Specific language impainnent (SLI) is a recognized disability characterized by

failure to develop language at an expected rate (Tager-Flusberg and Cooper, 1999).

Accordingly, the onset ofSLI is during the preschool years. The best estimate of

population prevalence for SLI is 7.4%, with 8% in boys and 6% in girls in the USA

(Tomblin et al. 1997). This disorder is also known as developmental aphasia (rarely used

Iately), developmental dysphasia, or developmentallanguage disorder (DLD), with the

DLD and SLI being the most popular terms in the UK and USA (Bishop et al. et al. 1992).

SLI is similar to other complex behavioral disorders in that there is no '~goldn standard for

diagnosis. The diagnosis in adults is particularly problematic (plante et al. 1996; Tomblin

et al. 1992), as is the case in other developmental childhood onset disorders (Smalley,

1997), because the impairment is generally less overt in adulthood. In addition, there is

no generally accepted test or structured interview to he used in arriving at a diagnosis of

SLI (Aram et al. 1993; Dunn et al. 1996; Plante, 1998).

The diagnosis of SLI is based on exclusionary and/or discrepancy criteria and is a

matter ofongoing debate (Tager-Flusberg and Cooper, 1999). Exclusionary criteria

commonly include mental retardation, peripheral hearing 1055 and neurological disorder,

17

although more subtle auditory, neurological, cognitive, and behavioral deficits remain

associated with the SU category (Bishop, 1992; Gauger et al. 1997; Goorhuis-Brouwer

& Wijnberg-Williams, 1996; Labey" Edwards, 1995; Lewis et al. 1993; Lubert, 1981;

Neils &~ 1986; Powell & Bishop, 1992; Plante et al. 1991; Plante, 1998; Redmond

and Rice, 1998; Tallai et al. 1991; Tomblin, 1989; Wright et al. 1997). Therefore"

notwithstanding the application ofthese exclusionary criteri~ the boundaries of the SLI

phenotype remain decidedly unclear, and uniform operational measures for these

exclusionary criteria are not established. With resPect to mental retardation" many studles

have accepted the nonverbal IQ criterion of 8S points or greater, using diverse

instruments, sorne ofwhich show different results when administered to the samc set of

subjects (Cole et al. 1994; Plante, 1998; Swisher et al. 1994). The cut-ofTvaluc of 85

points is debated on various grounds, including that it was originally proposcd not ~ a

nonverbal IQ criterion per se but to compensate for the expected low verbal IQ WhlCh

would otherwise result in a general IQ of 70 points or less, meeting the excluslona~

criterion ofmental retardation (Gopnik and Goad, 1997; Plante, 1998; Tager-Flusherg

and Cooper, 1999). For issues regarding the use ofIQ in discrepancy criteria. sc:e the next

paragraph. Because most studies with reported IQ values used a cut-otTof 85. therc IS

presently insufficient data to evaluate with any certainty the inf1uence~ or lack thc:rcof. of

nonverbal IQ below 8S in SLI (plante, 1998).

Discrepancy criteria are more controversial than exclusionary criteria (Aram et al.

1993; Dunn et al. 1996; Plante, 1998). The principal notion is that SLI can be diagnosed

in tenns ofa discrepancy between receptive and/or expressive language function and

sorne other cognitive fonction, i.e. discrepancy between language test score and mental or

18

chronological age. This rationale bas been adapted to a variety ofmeasures ofnonverbal

performance and language, with diverse operational criteria (plante, 1998). The major

issues regarding discrepancy criteria concem the psychometrie and statistical

shortcomings ofthose language tests which are presently use~ and the corresponding

paucity ofoperational definitions of language impairment (ASHA, 1989; Aram et al.

1993; Ounn et al. 1996; Plante, 1998). The rationale behind the concept ofcognitive

referencing often used in discrepancy diagnoses bas been questioned on various grounds.

These include weak conceptual rationale for the direct influence ofcognition, as

measured by IQ, on language skills, psychometrie issues regarding the significance of the

discrepancy, lack ofdifferences in treatment outcome stratified by IQ status, and

variation in cognitive ability, as measured by IQ scores, over lime (Casby, 1992; Cole et.

aL 1990; Francis et al. 1996; Krasowski and Plante, 1997). Discrepancy constructs can

show low sensitivity and Low specificity with respect to clinical diagnosis (Aram et al.

1992; Aram et al. 1993; Dunn et al. 1996).

In summary, the most widely used definition of SLI pertains, for the most part, to

overt exclusionary aspects, while the commonality with respect to the inclusion is largely

limited to the fact that subjects have received clinical treatment. Limitations of this

imprecision, and the need for additional multidisciplinary work on the fonnulation of

more precise SLI criteria, are recognized (Tager-Flusberg and Cooper, (999).

Etiology of SLI

Family history studies comparing the risk to relatives ofSLI probands and

contrais, which utilize defined inclusion and exclusion criteria, are presented in Table 1.

19

e

Table 1. Proportions ofAffected First-Degree Relatives in SLI Probands and Control Subjects

e

Authors SLI Control SLI Proband Selection Criteria(N) (N)

Diagnosis in Relatives SLI Control

Neils and Age 4-5.1Iyr. Normal pure tone audiornetric sereen; at Questionnaire to parents on:Ararn least 85 performance IQ score on WPPSI; absence offrank pronunciation, stunering, reading and(1986) 74 36 neurological disorders; developrnentallanguage disorder language. 20' .03'

diagnosed by certified speech~language pathologist andscore of< 85 on the TOLD test; absence ofstructural oraldeviation.

Tornblin Second grade children rated by speech Questionnaire to parents on:(1989) and language clinician al least 2 on the language seale of articulation and language problern.

51 136 ISRS, sorne ofwhorn were identified as learning disabled; and ever having clinicat treatment; no 23 .03none were diagnosed or placed in programs for rnentally hearing or mentalretarded or round ta he hearing impaired. impainnent.

Tallal, Age 4.0 - 4.11yr. Nonverbal perfonnance IQ score 8S or Questionnaire to parents on: language.Ross and better on LIPS; mean language age (trom standardized reading, writing and academicCurtis 62 50 expressive and receptive seores) at least Iyr below both achievement. Help provided to both(1989) chronological and performance mental age; no more than parents in filling the questionnaire with 42' .19'

20dB loss in either ear at 250~6000 Hz; no motor subsequent review.handicaps or oral structural or motor impainnents; notautistic by DSM III; no known neurological disorders onthe pediatrie neurological exam.

•Average proportion ofaffected first-degree relatives in families.

20

e

Table 1 continued

e

Authors Stl Control Stl Proband Selection Criteria Diagnosis in Relatives Stl Control(N) (N)

Lewis, Age 4..(jyr. Severe phonological disorder diagnosed by Parental interview and questionnaireEkelman scoring at least 2 SD below the Mean on PAT and on: speech/langu8ge problems,and Aram 20 20 employing at least three phonological processes; nonnal stuttering, leaming disabilities and(1989) pure tone audiometric screen at 25dB HL ISO for 500, dyslexia; extended relatives not .26 .05

1000, 2000, 4000 and 6000Hz bilaterally and fewer than 5 differentiated by the degree ofreported episodes ofotitis media; normal peripheral speech relationship.mechanism structure assessed by OSMSE; performance IQscore of80 or above on the WPPSI; absence offrankneurological disorders as reported by the parent.

Rice, Haney Age 4.S-S.5yr. Particular grammatical impainnent-extended Parental interview on speech/languageand Wexler optional infinitive. Score below 85 on the PPVT-R disorders and readingfspellinglleaming(1998) 31 67 receptive language measure; below age expectation for disorders.

expressive language measured by MLU; score above 85 on .26 .13the Columbia Mental Maturity Scale; no major articulationproblems on the GFTA test; passed hearing screening; noneurological, socio-emolional or behavioral disorders asreported by speech!language pathologist.

21

The phenotype in relatives is often broadly defined, including learning disorders and

other communication disorders, ail ofwhich are ofte~ due to their striking associations

and the lack ofclear phenotype bounclaries, referred to as language..leaming disorders

(AACAP, 1998). Despite this problem and the concomitant methodological heterogeneity

that can explain some discrepant results, the principal overall conclusion ftom these

studies is that the proportion ofaffected first-degree relatives is consistently higher in SLI

probands than in control subjects.

However, familial aggregation does not constitute genetic etiology; as potential

environmental familial influences must also he considered. One way ofdoing this is to

conduet twin studies, on the rationale that MZ and DZ twins share similar environments,

but differ in genetie relatedness. A receot English language twin study reponed pair-wise

Ml concordance of0.54 and DZ concordance of0.30, for DSM..ill-R developmental

language or articulation disorder (Bishop et al. 1995). Proband-wise concordances were

0.70 (68/97) and 0.46 (16/35) respectively. In the cited study, parental report and medical

records yielded no evidence ofmental retardation, sensorineural hearing loss, structural

abnormality ofarticulators, serious visual impairment or a medical sYndrome. Therefore

this sample is comparable to other SLI samples. Another recent English language study

reported proband-wise concordance for test..based poor language status of 0.96 (82/85) in

Ml and 0.69 (24/35) in Dl twins (Tomblin & Buckwalter, 1998). These subjects passed

a hearing screening, and did not show mental retardation or other developmental and

behavioral disorders. Prior twin studies ofspeechllanguage measures were less

informative for the SLI category due to diagnostic limitations (Lewis and Thompson,

1992; reviewed in Bishop et al. 1995; Tomblin and Buckwalter, 1998).

22

•

Environmental influences, other than parental language input (Kuhl et al. 1997),

mayalso he important in SU Differences between SU children and controls were found

for parental tobacco smoking and breast feeding (Tomblin et al. 1997a).

Genetic Mapping Srumes and SL!. A segregation analysis ofSLI failed to

distinguish between a major gene and a multifaetorial transmission (Lewis et al. 1993),

in a sense confinning complex etiology that could have been hypothesized from the

general absence ofMendelian inheritance patterns in this poorly defined diagnostic

category. Tomblin and Zhang (1999) briefly noted that a major dominant locus model

was supported in the segregation anaIysis ofSLI in 58 families. A fully penetrant

autosomal dominant genetic locus in the 7q31 region was mapped to the phenotype of

severe speech/language impairment with speech and orofaciaI dyspraxia in a lΠfamily,

where sorne ofaffected individuals aIso had nonverbal IQ <85 but>70 points (Fisher et

aI. 1998; Vargha-Khadem et al. 1995). This family is clearly not representative ofmost

SLI families, because most families do not show simple Mendelian inheritance. However,

a recent report descnoes two different apparently balanced chromosome rearrangements

in the same region, one in the subject with specifie language impairment (and Iacking

reliable confirmation ofspeechllanguage impairment in extended relatives), and the other

in a different subject with autism (Warburton et al. 2000). The 7q31 region May therefore

harbor a gene, or genes, that are involved in bath autism and SLl, although the possibility

ofdifferent genes for different phenotypes cannot he excluded. Molecular genetic

mapping studies ofSLI are yet to be reported.

23

•

2.2. POTENTIAL FOR IMPROVEMENT

OF PHENOTYPIC DEFINITION IN SU

The clinical phenotype ofSLI is both poorly defined and at the high hierarchical

level ofdevelopmental organization, quite distant trom the level ofnucleotide sequences

in the genetic material. Consequently, different genes may he associated with ditIerent

components ofthe SLI phenotype. It is therefore important to define more homogenous,

precisely specified phenotypes within the overall SLI category in arder to facilitate

genetic and other research ofthis complex phenotype.

Many, but not ail, clinicians distinguish afIeeted individuals by clinicai SYndromes

more detailed than the basic expressive/receptive distinction in the diagnosis of SL!

(Rapin & Allen, 1983; Rapin, 1996). The DSM-IV defines expressive, mixed expressive­

receptive, and phonologicallanguage disorder (APA, 1994). The ICD-I 0 defines

expressive language disorder and receptive language disorder. These categories, however,

are not widely used in research, but are only similar to the common definition ofSLI

described previously. Dysarthria denotes impaired speech articulation caused by motor

muscular deficit (Rapi~ 1996), and children diagnosed with this impairment are

generally not considered to be SLI children, although motor speech impairment does not

necessarily account for language deficits (Rice, 1999). The most common mixed

expressive/receptive language disorder in SLI is syntactic-phonological syndrome,

denoting poor phonology, syntax, and morphology (Rapin, 1996). Expressive language

disorders are: verbal dyspraxia, a severe expressive language problem with sparse output

and very poor phonology; and speech-programming deficit disorder, fluent with jargon

24

(Rapin, 1996). Disorders considered to he ofhigher arder processing nature are: lexical

deficit disorder, with ward finding and comprehension problems; and semantic-pragmatic

syndrome, with correct phonology and syntax accompanied by inappropriate use of

language, indicating difficulties with social aspects of language (Rapin, 1996). There May

he transition between these syndromes over time (Ramsden & Botting, 1999),

emphasizing the complex developmental character ofSU. In a single study, SU children

with expressive language deficit had a higher proportion ofaffected family members then

children with expressive and receptive language deficit (Lahey & Edwards, 1995).

In addition to clinical speech/language syndromes that May potentially be used to

increase homogeneity among affected individuals, there are more "molecular''l

phenotypes associated with SLI which may facilitate identification ofvulnerability genes

in this complex disorder. For example, auditory event related potentials, and phonological

processing deficits, are associated with both SLI and dyslexia (Fletcher et al. 1999;

Leppanen & Lyytinen, 1997; Riee, 1999). Distinct morphological strueture of language

related brain areas is associated with SLI (plante, 1996). Moreover, more specifie

linguistic components, or non-linguistic abnormalities present in SLI children, could in

principle he used to improve phenotype definition in SL!. Various hypotheses conceming

the "core" nature ofSLI were proposed on the basis of linguistic and non-Iinguistic facets

of the SLI phenotype. These include deficits in grammatical neural substrates, subtle and

multiple infonnation processing defieits, generalized intellectual defieit in conceptual

development or leaming strategies (Bishop, 1992; Clahsen, 1989; Curtîss and Tallai,

1991; Gopnik & Goa~ 1997; Leonard, 1989). However, recent views of SLI are more

oriented towards heterogenous etiology influenced by different factors that are neither

25

necessary nor suffieient for expression ofthe elinical SLI phenotype, rather than the

single '~core" explanation for the majority ofSLI cases (Bishop et al. 1999; Rice, 1999;

Tager-Flusberg and CooPer, 1999). For the purpose ofdetining more homogenous

phenotypes in SLI, the present work concems specifie components of impaired

grammatical competence, an~ in a separate study, the presence ofattention

defieitlhyperactivity behavioral problems in SU ehildren. These aspects ofSLI are

descnèed in more detail, below.

2.3. SPECIFIe COMPONENTS OF THE GRAMMATICAL

PHENOTYPE IN SLI

Although there is no consensus on partieular etiological hypotheses, numerous

studies coDSistently demonstrate that impainnent in the domain ofgrammatical

morphology represents a predominant aspect oflinguistie Performance in SLI ehildren

(Gopnik, 1999; Leonard et al. 1999; Oetting & Horohov, 1997; Rice, 1999; Rice &

Oetting, 1993; Riee & Wexler, 1996; Rose & Doyle, 1999). Until recently, there was no

substantial evidenee for a specifie grammatical marker that would accurately diseriminate

SL! children from controls (reviewed in Rice, 1999), leading to a proposition that SLI

essentially represents a developmental delay that falls within a broad range oftypical

language development in children (Leonard, 1987). More recent studies, however, have

identified finite verb morphology, in particular Tense marking, as a promising clinical

Marker in English speaking SLI children (Bedore & Leonard, 1998; Leonard et al. 1999;

26

Oetting & Horohov, 1997; Rice, 1999; Rice et al. 1995; Rice et al. 1998; Rice & Wexler,

1996).

Finiteness is a property marked on verbs, which can appear in finite and infinite

forms: finite forms are those marked for Tense and grammatical agreement (Rice, 1999).

In a study ofchildren receiving preschool intervention services, and meeting aIl inclusion

and exclusion criteria for SLI, Rice & Wexler (1996) found two types ofevidence which

argue in favor ofverb Tense marking (morphemes -s third person singular, -ed regular

past, BE, and 00 ) as a specific clinical marker for SLI children. Fi~ 37 ofthese 5yr old

SLI children showed low levels ofaccuraey for morphemes that mark Tense in relation to

45 age matched controls, and aIso in relation to 40 of3yr old controls matched for MLU

(the Mean length ofutterance). The latter control group was thereçore at an equivalent

language level as the SLI children on MLU (Riee & Wexler, 1996). This finding argues

against the view ofSLI as a developmentallanguage delay without qualitative

grammatical distinctions. Second, SLI children were impaired specifically on a set of

grammatical morphemes defined by the linguistic fonction ofTense, but not for

grammatical morphemes unrelated to Tense, including regular is plurals, the prepositions

in and on, and the progressive -ing on the verbs (Riee & Wexler, 1996). This result

suggests that the impairment ofgrammatical Tense marking function May he a relatively

specifie distinguishing factor contributing to the overall SLI phenotype. Auditory

processing-deficit was inconsistent with specific errors restricted to Tense marking in

these SLI children. Children with the Williams syndrome display a nearly adult level of

Tense marking, although their intellectual competencies are far below SLI children.

27

(Ricet 1999). These observations raise the possibility that specifie neural substrates

related to grammatical aptitude May contribute to the impainnent in Tense marking.

The status ofverb Tense marking as a clinicaI Marker was also examined by

Bedore & Leonard (1998}t in a discriminant function analysis ofSU children, ages 3.7yr

- 5.9Yft diagnosed sirnilarly with respect to inclusion and exclusion criteria. Linguistic

constructs including a finite verb morpheme compositet a noun morpheme composite,

and the Mean length ofutterance in morphemes, were used to discriminate 19 LI children

from 19 age-matched controls in a first study, and 6 additional SLI children and 6 novel

controls in a second experiment (Bedore & Leonar<l 1998). The finite verb morpheme

composite (regular past tense intlectionst regular third persan singular present inflections,

and copula and auxiliary be forms) showed the best combination ofsensitivity (>84%)

and specificity (100%), which was not substantially improved by the addition ofother

two variables. Tempered by the small number ofsubjects, these results indicated that

verb Tense marking may be an optimal clinical Marker among different components of

impaired language which were examined.

While the verb Tense marking is best documented, it may not he the ooly relevant

grammatical marker phenotype in SLI (Rice & WexIer, 1996). Overall grammatical

competence is a complex phenotype that comprises a number oftheoretically different

aspects of language comprehension and production (Gopni~ 1999). Accordingly, it is

recognized that global characterizations of language aptitude May not be as

neurologically and genetically illuminating as are carefully and precisely specified

distinctions, which may in tum provide the framework for relating linguistics to a more

molecular level of investigation (Rice, 1999). In the previously noted twin study ofSLI

28

children, Bishop and coworkers (1995) reported high heritability estimates for Word

Finding, for a Test for Reception ofGrammar, and for the Comprehension test (ail

estimates -1). Substantially lower heritability (-0.56) was reported for Repeating

Sentences, suggesting that sorne specifie aspects of linguistie competence May be under

greater genetic control than other aspects.

The above considerations suggest that the analysis ofmore specifie aspects of

linguistic competence can he a promising strategy for identification ofmore homogenous

phenotypes in SLI, which might eventually facilitate both the multifaceted understanding

ofthe complex end-point behavioral phenotype and the identification ofpotcnllal gcncuc

vulnerability loci. With this rationale, the present manuscript examines sibling

resemblance for specifie theoretically derived components ofgrammatical com~tcnce ln

families of SLI children, including competence in verb Tense marking, among olhcrs

The manuscript, submitted to the Journal ofNeuro1inguistics, is entitled ··Sibhng

Resemblance for Specifie Components ofLinguistics Competence in Famihes of

Speech/Language Impaired Children".

2.4. THE SLI PHENOTYPE

AND ATTENTION DEFICITIHYPERACTIVITY

Attention deficitlhyperactivity disorder (ADHD) is a common childhood onset

disorder with a population prevalence of2-12% (reviewed in Greenhill, 1998). and

substantial evidence of familial and genetic etiology (family, m'in and molecular genetic

studies reviewed in Rutter et al. 1999). Tbere are a variety ofoperational procedures for

29

arriving at diagnosis ofADHD (Conners~ 1998; Greenhill, 1989). DSM...IV (APA, 1994)

provides two sets ofoperational criteria, corresponding to inattention and

hyperaetivity/impulsivity~ to define a combined subtype~ predominantly inattentive

subtype~ and a subthreshold category. Comorbidity ofADHD with other psychiatric

disorders is notable~ including oppositional defiant disorder or conduct disorder~

depressive disorders~ anxiety~ bipolar disorder, and leaming disorders, with reading,

spelling, and arithmetic being studied most often in the latter category (reviewed in:

Angold et ai. 1999; Pliszka, 1998).

Attention DeficitIHyperactivity in SpeechlLanguage Impaired Children

The comorbidity between speechlIanguage disorders~ not defmed with respect to

SLI criteria, and attention deficit/hyperactivity disorder bas been documented in several

studies. For example~ Beitcbman and coworkers (1986) found that 30.4% of 135 children

in a population-based sample with speechllanguage disorders and 4.5% of 137 control

children had Attention Deficit Disorder by OSM-ID criteria. In the same study, 15.7% of

134 speech/language impaired children and 9.4% of 138 controls had a hyperactivity

score>2SD above the nonn on the Conners Teachers Questionnaire. Cantwell and Baker

(1987) studied clinically identified children with a) "pure~' speech disorder(voice,

articulation, fluency disorder), b) speech and language (expressive~ receptive or

processing) disorder, and c) language (expressive, receptive, or processing) disorder. The

proportions ofchildren in each of these three groups who aIso met criteria for attention

deficit disorder (based on interviews and behavior rating scales) were 10%, 23%~ and

33%, respectively, suggesting that attention deficit was not strongly associated with

30

Upure,t speech disorders as defined in the study. Conversely, language disorders are

among the major comorbid conditions in attention deficit disorder (Cantwell, 1996;

Cohen et al. 1993; Love et al. 1988). Love and coworkers (1988) found that two-thirds of

clinically identified children with DSM-m attention deficit disorder aIso had a language

disorder. Cohen and coworkers (1993) reported that bath children with previously

identified and unsuspected language impairments had symptoms associated with ADHD.

Attention DeficitIHyperactivity in SLI Children

Aram, Ekelman and Nation (1984) reported a longitudinal study ofEnglish­

speaking language impaired children who passed a pure tone audiometric test, and did not

have neurological or craniofaciai abnormalities. Among 20 subjects, 15 had nonverbal IQ

>85 points. The 14 clinically diagnosed speecbllanguage imPaired boys, ages 13-16yr,

were rated by parents as more hyperactive than expected for a nonnative control group

(P<O.OI).

Goorhuis-Brower and Wijnberg-Williams (1996) reported that Il of 14 Dutch­

speaking children, ages 6.7-9.7yr, showed attention problems based on questionnaires for

parents and teachers. These children were clinically diagnosed with SLI 4 years earlier,

having no hearing loss, mental retardation, neurological disorder, general medical

problem, or any psychiatrie disorder including AOfID. It is not clear, however, that these

children did not have any subclinical symptoms associated with attention

deficitlhyperactivity at the time of SLI diagnosis.

Redmond and Rice (1998) studied 17 English-sPeaking SLI children (11 boys and

6 girls) and 20 age-matched controls at ages of -6yr and -7yr. SLI children were

31

clinically diagnosed, had normal intellectual fonction, normal hearing, and no major

articulation problems. The Achenbach Child Behavior Checklist and the Teacher Report

Form were used to obtain ratings fram parents and teachers. At both ages, only the

teachers reported more attention problems in SLI children. At first rating, the T-scores

and SO (in brackets) for attention were 58(9) in SLI children versus 53(4) in controls~ as

rated by teaehers. At the second rating a year later, these values were 57(7) versus 53(4).

Taken together, evidence noted so far suggests that the association of

speechllanguage disorders with attention deficitlhyperactivity May persist when the: SLI

criteria are employed.

Attention DeficitIHyperactivity in SL! Cbildren and Familial Aggregation

Ofparticular further interest is the study ofTaIlal and coworkers (199 J ). who

rePOrted that SLI probands who had at least one affected parent were more oftcn ralcd as

having attention/hyperactivity behavioral problems. The SLI probands were dlagnosed

using the discrepancy ofat least 1yr between language age computed from standardazed

scores, and performance mental age and chronological age. They also had performance

IQ ~ 85, normal hearing acuity, no motor imPairment of articulators~English language

background, and were not autistic by OSM-ill-R criteria. The SLI probands wcre deemed

ta be family history positive ifat least one parent reported having had one or more of

following problems: a) below average or impaired school achievement in reading or

writing, b) placement in a remedial class for reading or writing, c) kept back a grade or

having failed a class, d) below average or impaired language development as a child, or

d) speech therapy. Among 23 SLI probands, 16 were family history positive and 7 were

32

family history negative. Scales developed trom factor analysis ofAchenbach parent and

teacher ratings showed that family history positive probands were more often rated as

"hyperactive" by parents (p<O.OO1) and more often rated as "inattentive" by teachers

(p<O.OS). Except from Donverbal auditory processing and attention, family history did Dot

differentiate between other profiles, including degree or Pattern oflanguage deticit,

general intelligence, academic performance measures, visual-spatial skills, speech-oral

motor abilities, and auditory competence as per audiological exam and brain stem evoked

auditory responses.

Notwithstanding the small sample size and ambiguous phenotypes inherent in the

current SL! diagnosis and the family history method, this study suggests the hypothesis

that anention/hyperactivity behavioral problems may provide a basis for delineating a

more familial phenotype within the SLI category. Based on these results, it can be

hypothesized that the risk to relatives ofSLI children with ADHD symptoms or diagnosis

May be higher than the risk to relatives of SLI children without these behavioral

problems. The Iogical next step is therefore ta compare these risks; the evidence in

support of this hypothesis would provide impetus for further familiaVgenetic studies of

the relationship between SLI an ADHD. This analysis is perfonned in the manuscript

entitled "'Attention DeficitIHyperactivity in SLI Children Increases Risk of

SpeechlLanguage Disorders in First-Degree Relatives", submitted ta the Journal of

Communication Disorders .

2.5. SUMMARY

Specific Language Impairment (SU) is a complex bebavioral disorder tbat is

gaining attention as a candidate for genetic mapping studies. The power ofthese studies

to identify correct linkage localization, and thence to detect specific genes, can be

enhanced by the use ofprecisely defined phenotypes that can alleviate ambiguities ofthe

clinical SLI diagnosis. The goal ofpresent studies is to explore phenotypes that May show

increased familial aggregation, using a) theoretically derived specific components of

grammatical competence; or, b) presence ofattention deticitihyperactivity behavioral

problems in SLI children. More familial phenotypes May eventually prove useful for

genetic mapping studies.

34

2(8). SIBLING RESEMBLANCE FOR SPECIFIC COMPONENTS OF

LlNGUISTIC COMPETENCE IN FAMILlES OF SPEECRILANGUAGE

IMPAIRED CIIILDREN

The present chapter consists ofthe following manuscript in submissio~ entitled

as above.

35

Sibling Resemblance for Specifie Components ofLinguistie Competence in Families of

Speech/Language Impaired Children

ILUA KOVAC1, MYRNA GOPNIK3

•ROBERTA M. PALMOUR1.2,·

Departments ofBiologyl, Human Geneties2, Psychiatrr, and Linguisties3 (ret.), McGill

University, Montreal, Quebec, Canada

1.2·Department ofPsychiatry, McGill University

Allan Memorial Institute, Research and Training Building Room 307

1033 Pine Avenue West, H3A lAt, Montreal, Quebec::, CANADA

Tel. (514) 398-7303; Fax (514) 3984370

E-mail: rnc23@musica.mcgiIl.ca

3Department ofLinguistics, McGill University

1085 Dr Penfield Avenue IDA lA7, Montreal, Quebec, CANADA

36

Abstraet

We examioed performance 00 specific linguistic tests in 23 English and French

speaking familles, recruited from clinical and other sources, ofchildren who met

following criteria for specifie language impairment (SLI): clinically diagnosed language

impairment without peripheral hearing 105s, mental retardation (nonverbal IQ~70),

neurological disorder, schizopbrenia or autisme Subjects, at least 9 years old, completed a

battery ofFrench or English language tests, including Derivational Morphology, Verb

Tense Morphology, Grammaticality Judgement, Syntaetic Comprehension., and Pointing.

Listening Comprehension and WUG pluralization test were analyzed ooly in the English

group. The Verb Tense Morphology(Real Words) and Verb Tense Morphology (Non-real

Words), respectively, showed non-parametric sibling correlations of0.39 and 0.35

(p<O.OS, 2-tailed) in 38 pairs (mixed gender) from 10 French test Pedigrees. In the

English group, Derivational Morphology showed significant 0.52 correlation in 41 sibling

pairs frorn the densely affected FE pedigree. After controlling for age, sibling correlation

for Verb Tense Morphology (Real Words) remained significant, and Derivational

Morphology correlation in the FE pedigree was borderline (p=O.OS). Impaired

grammatical morphology is a predominant aspect of SLI., and the present study, which

requires independent replicatio~ suggests that Verb Tense Morphology and Derivational

Morphology warrant particular attention in future familial and genetic studies.

Keywords: Verb tense, Familial resemblance, Specifie phenotype

37

1. Introduction

Children diagnosed with speechllanguage impairment and lacking peripheral

hearing loss, mental retardation, or neurological disorder are commonly referred to as

having specifie language impainnent (SLI), or developmentallanguage disorder, although

more subtle auditory, neurological, cognitive and behavioral deficits remain associated

with the SLI category (Lubert, 1981; Neils &, Aram, 1986; Tomblin, 1989; Tallai et al.

1991; Bishop, 1992; Powell &, Bishop, 1992; Lewis et al. 1993; Labey &, Edwards, 1995;

Goorhuis-Brouwer &, Wijnberg-Williams, 1996; Tomblin et al. 1997a; Wright et al. 1997;

Redmond &, Riee, 1998; Plante, 1998). The SLI is a complex disorder with documented

familial aggregation, influeneed by bath genetic and environmental factors (Lewis et al.

1993; Labey &, Edwards, 1995; Bishop, North, &, Donlan, 1995; Tomblin et al. 1997b;

Riee, Haney, &, Wexler 1998). Recently, a fully penetrant autosomal dominant genetic

locus was mapped in a single pedigree characterized with severe speeeManguage

impainnent accompanied by orofacial dyspraxia in ail atTected individuals (Vargha­

Khadem et al. 1995; Fisher et al. 1998). However, SLI families typically do not show

simple Mendelian inheritance (Lewis et al. 1993).

Different factors, including output mechanisms, information processing,

grammatical mechanisms, and generally impaired conceptual developmen~ were

proposed as separate "core"" explanations of SLI (reviews in Bishop, 1992; Gopnik &,

Goad, 1997). However, because the phenotype ofgrammatical behavior is at a highly

complex hierarchicallevel ofdevelopmental organization, is likely to he influenced by

Many factors. It is increasingly recognized that there May he multiple synergistic fac~ors

38

which are neither necessary nor sufficient for expression ofthe phenotype ofSLI, i.e.

subde auditory processing deficits, or a nonverbal IQ between 70 and 85 points (Gopnik

&. Goad, 1997; Plante, 1998; Bishop et al. 1999; Tager.Flusberg &. Cooper, 1999; Rice,

1999). Accordingly, the analysis ofempirical data collected with test batteries designed

to probe theoretically derived linguistic components ofthe SLI phenotype could lead to

the development ofmore specific phenotypes. Ifthese phenotypes were etiologically

more homogenous they might increase the power to detect genes with more specifie

effects (Lander &. Sehor~ 1994). An example ofthis strategy is genetie research in

dyslexia (specifie reading disability), another complex disorder with ratber similar

exclusionary aspects ofphenotype definition (Fisher et al. 1999; Gayan et al. 1999;

Grigorenko et al. 1997; Penningto~ 1997). Component skills, such as phonological

decoding and orthographie coding, generally showed stronger evidence for linkage to

chromosome 6 than word recognition or reading performance, which are higher order

processes influenced by other factors in addition to these component skiUs (Fisher et al

1999).

The multidisciplinary Genetie Language Impairment Project (GLIP) at the McGill

University (Myrna Gopnik, PI) included a battery oftests designed to evaluate specifie

theoretically derived components of linguistic competence in families with SLI children

(Gopnik, 1999; Rose & Doyle, 1999). These linguistic tests were adapted for English,

French., Greek, and Japanese, so that overall results could he comparable across

languages. The purpose ofthe present study is to examine sibling resemblance for

specifie components of linguistic competence assessed by the English and French GLIP

39

test batteries. This examination may indicate specifie phenotypes of interest for further

familial and genetic studies.

2. Subjects and Metbods

2.1. Subjects

The present study included 23 families selected for direct language testing,

accordingto the criteria Iisted below, within the McGill University Genetie Language

Impairment Project (GLIP, Myrna Gopnik, PI). Ofthese 23 famifies, 14 families were

from the pool of 156 families initially identified through parental response to an

announcement in the newsletter ofthe Association ofQuebec Dysphasie Children

(AQEA). The AQEA comprises families ofchildren elinically diagnosed with

speechllanguage disorder. Ofthe remaining Il families, 9 were identified through

elinician's (from the Montreal Children's Hospital, or the Children's Hospital ofEastern

Ontario in Ottaw~ or the Vanguard Sehool in Montreal) referral of9 cases meeting the

selection criteria listed below, while 2 families were self-referred.

As reported previously (Gopni~ 1999; Rose & Doyle, 1999) information from

clinicians and Medical records was used to identify probands based on following criteria:

a) confirmed diagnosis of language impainnent by a speech/language pathologist, b)

normal hearing (25db), c) performance IQ of 70 and over, d) no presence offrank

neurological signs, e) no evidence ofautism or schizophrenia by the DSM m-R criteria.

40

Probands did not bave other serious Medical conditions tbat might have caused

speecb/language impairment.

At least one impaired first-degree relative as judged by clinical diagnosis7present

or past family history report ofspeechllanguage problem, speech therapy7 readinglwriting

problem, or an ongoing educational/school problem was generally required for enrolment

ofthe family for language testing. One family with 6 children and no first-degree

relatives of the SLI proband known to he impaired was a1so enrolled.

Healthy controls with no known family history ofspeech/language impairment

were also recruited for both English (N =22) and French (N = 8) language testing

(Gopnik, 1999; Rose & Doyle71999).

2.2. Methods

2.2./. Direct Linguistic Testing

Comprehensive linguistic accounts ofthe testing procedure and perfonnance of

these English and French speakïng subjects are reported elsewhere (Gopni~ 1999; Rose

& Doyle, 1999, and references therein). Here we provide a briefsummary. The GLIP

Linguistic Profile Test Battery was adapted from the Bilingual Aphasia Test (paradis,

1987) for the English and French subjeets examined in this report, and for the Greek and

Japanese subjects not examined here. The test battery was constructed to address a

number ofhypotheses about the nature and cause ofSLI (Gopnik, 1999). Sorne ofthe

linguistic tasks required an understanding ofabstract concepts such as grammaticality.

Subjects under the age of9 yr. were not always able to complete aU sections ofthe test

41

•

battery (Gopnik, 1999; Rose &, Doyle, 1999). Therefore, thase subjects whose test scores

are analyzed in this paper were at least 9 years old at the time oftesting. Within both the

English and French Linguistic Profile Battery, some families were identified through the

AQEA and some were identified in other ways. In the English test group, 55 of71 tested

subjects were included in the analysis, and in the French test group 67 of79 tested

subjects were included Excluded were subjects younger than 9yr at testing, 1 adoptive

father from the extended family in the English test group, and 1second-degree relative in

the French test group because of unusual response to testing, for example always giving

an affirmative answer to 29 Grammaticality Judgement questions (data trom Rose &,

Doyle, 1999). The analysis included 12 probands from Il ofthe 14 families identified

through the AQE~ and 4 probands from the 9 other families noted in the subjects

section. Many families used both French and English language in communication as

commonly found in Quebec, and in some families test languages ditTered among family

members, while 4 subjects, including 2 probands, participated in both test languages.

Further details conceming the structure ofthis analyzed sample by family, test language

and degree of relationship among tested family members are provided in the Appendix.

Table 1 briefly summarizes the tests provided for this report, including the

relevant language, areas ofcompetence that were targeted, and the test stratification into

sub-tests with respect ta types of input, as described more extensively elsewhere (Gopnik

1999; Rose & Doyle, 1999). Each test was explained to subjects before the aetual scored

trial began; subjects were also given trial examples that were not scored.

Grammaticality Judgment. Subjects were asked ta judge whether a sentence read

by the examiner was a correct sentence, and to verbally correct the sentence ifnecessary.

42

•

Table 1

Language Tests

Test (Language) Area ofCompetenœ Sub-tests

Derivational Morphology producing derivation ofword

(English and French) morphology in a sentence no sub-tests

Verb Tense Morphology producing change ofverb tense in a Real Word Sentences

(English and French) sentence Non-word Sentences

Grammatical Sentences

Grammaticality Judgement and recognition ofgrammatica1ly correct Ungrammatical Sentences

Correction sentences and producing correction of Correct Jud~ement

(English and French) ungrarnmatical sentences (English onl)·,

Correct Correction

{English onl~ •

Syntactïc Comprehension comprehension ofsyntaetically CanonicaJ Senlences

(English and French) complex sentences Non-canorncal Sentences

WUGTest Real Ward Sentences

(English ooly) producing noun pluralization Non-word ScnlcncO

Painting comprehension ofplural and singular

(English and French) no sub-tests

Listening Comprehension comprehension of temporal sequence

(English ooly) eventsy causal relations no sub-lests

43

Both ofthese responses were required to he correct for a positive score with

ungrammatical sentences. An English language example ofa grammatically incorrect

sentence is "Yesterday 1walk home"" and the French language example is "Le garçon

sourit la fille." There were 32 sentences in the English test and 30 sentences in the French

test, balfofwhich in either language were grammatically incorrect. In the French

language" 1 ungrammatical sentence was removed from score calculations by GLIP

testers because it was a problem for most speakers (data from Rose & Doyle" 1999). The

test score was the number ofcorrect responses. In the English language" scores for

Correct Judgement out ofaU 32 sentences and Correct Correction out of 16

ungrammatical sentences were also obtained

Derivationa/ Morph%gy. Subjects were asked to verbally complete taped

sentences using a ditTerent morphological forro ofthe word from the preceding complete

sentence. The English language example is "That makes a lot ofnoise. It is very __

(noisy). The French language example is "Mes amis font de la magie. Ce sont des __

(magiciens). There were 10 items in the English language and 12 items in the French

language. The test score was the number ofcorrect responses.

Verb Tense Morph%gy. Subjects were asked ta verbally complete taped

sentences by changing the tense of the verb. The English language example is '~very day

he plays bail. Yesterday he (played bail). The French language example is "Le

bébé a pleuré toute la nuit. Encore maintenant il (pleure). In both languages some

sentences contained non-words and subjects were asked to complete the sentence as if

those were real words" as in the English language example "Yesterday he [dizd] the

cookies. Right DOW he (is dizing).n The rationale for this stratification here, and in

44

the WUG test (see below)~ was that Real Words cao he memorized over time as a whole

and correctIy produced in the appropriate form without implicit knowledge of

grammatical rules; hence Non-real Words might reveal the lack ofgrammatical

competence more successfully (Gopnik, 1999; Rose & Doyle~ 1999). There were 12

sentences with the existing verbs and Il sentences with non-existing verbs in the English

language. In the French language there were 12 ofeach such sentences respectively. The

test score was the number ofcorrect responses.

Syntactic Comprehension. Subjects were asked to touch or say the number ofa

picture depicting the meaning ofa sentence read by the examiner. There were 8 canonical

and 14 non-canonical sentences in the English language, and 9 and 16 ofthese sentences

respectively in the French language. The test score was the number ofcorrect responses.

The English language example of the canonical sentence is "The girl washes the woman",

and the example of non-canonical sentence is "ft's the girl who the woman washes." The

French example of non-canonical sentence is "C'est la fille que le garçon pousse. (It is

the girl whom the boy pushes)".

The WUG Test. This test was administered only in the English group. Subjects

were shown a picture and told the name ofan object in the picture, repeated once, i.e.

"This is a chair. Chair." The next picture showed two ofthese objects and subjects were

asked to name them in plural~ i.e. "These are chairs". Some non-existing words were also

used and subjects were asked to respond as if those were rcal words~ i.e. "This is a wug.

Wug." "These are wugs." There were 10 items with existing words and 10 items with

non-existing words. The test score was the number ofcorrect responses.

45

•

Listening Comprehension. In this test from the English group, subjects were read

a short story and were then asked five questions about what bappened in the story. The

questions were: (1) Where were the boy and bis sister? (2) Wbat day ofthe week was it?

(3) What did the boy buy her? (4) Why did the boy buy an ice cream for bis sister? (5)

Why dido't the girl eat the ice cream? The test score was the nomber ofcorrect responses.

Pointing. In this test, subjects were asked to point to the pieture representing a

ward spoken by the examiner, either in singular or plural form. There were 24 items in

.the English and 16 items in the French language. The test score was the number ofconeet

responses.

2.2.2. S/atistica/ Methods

Properties of the scale measured by the administered language tests are not weil

understood. Therefore, the primary methods ofdata analysis were robust non-parametric

methods that require ordinal rather than interval scale ofmeasurement. The Wilcoxon

Signed Rank test for paired samples (Snedecor, 1956) was used to compare language test

scores in cases and controls, individually matched for age and sex without reference to

test scores. Due to the small number ofcontrols, particularly in the French b'fouP. some

reportedly normal subjects from families with SLI children were used as age- and sex-

matched controls. The potential drawback ofthis approach is that sorne of thc:se subJects

May have subtle language difficulties that could emerge at testing, making for a more

conservative comparison. Spearman's rho test was used to examine correlations between

test scores within the English and French test battery. Test score relationships with age

and gender were examined excluding probands, who were young and predominantly

46

males, and would tberefore bias these relationships. Speannan's rho test was used to

examine the correlations oftest scores with age, and Mann-Whitney U test was used to

compare age and test scores by gender.

2.2.3. Sib/ing Resemb/ance

Sibling resemblance for language test scores was evaluated using the Speannan's

rho correlation. A nonparametric method was chosen because it does not depend on the

assumption of interval seale ofmeasurement, and therefore allows for robust

interpretation ofresults. Moreover, we used ail possible sibling pairs in order to

maximize the utility ofthis data set through increased sample size, while acknowledging

that obtained correlations may he overestimated in comparison to statistically correct use

ofonly independent sibling pairs (Neale & Kendler, 1995).

There were 47 and 43 possible sibling pairs in the English and the French group

respectively, not counting 1 twin pair (purportedly MZ) in the French group. In the

English group, 41 of47 pairs were from the single extended FE pedigree known to he

densely affected and hence not representative ofSLI famifies. Because the remaining 6

sibling pairs contribute little information, and on the other hand might potentially

confound the interpretation of results, only the 41 sibling pairs ftom the FE pedigree were

analyzed in the English group. Moreover, 5 other sibling pairs ftom the FE pedigree that

were tested in the French language were excluded ftom the French group, for the reasons

noted above. Therefore, a total of41 and 38 sibling pairs were analyzed, originating

respectively ftom a single FE pedigree tested in English and 10 pedigrees tested in French

test.

47

•

The power for detecting a correlation with an etfect size of0.30 or 0.40,

conventionally referred to as medi~ was -50% and -7()oA. respectively, calculated for

the significance level of0.05 in 2-tailed tests with 41 sibling pairs in the English group

(Welkowîtz et al. 1991). For the 38 sibling pairs in the French group, the corresponding

power values were -45% and -7()oA.. Because the available sample sizes for other types of

relative pairs provided little statistical power, only sibling pairs are included in the

present study. In order to examine whether sibling correlation for age at testing might

potentially account for significant Don-parametric sibling correlations, in those instances

partial correlations using normalized Z scores (necessarily assuming interval scale of

measurement) were also computed

Although this report includes multiple statistical tests, most of the tested variables

are partly correlated, reducing the rate of inflation offalse positive results. As the

intention ofthis study is to provide hypotheses for further confirmatory research, we

consider as significant ail comparisons at the 2-tailed 0.05 level and discuss them in view

of relevant literature.

3. Resulu

3.1. The Population

The age at testing of 14 probands (the oldest affected child, in the case offamilies

with multiple clinically diagnosed siblings) trom 14 AQEA families ranged from 6.16 to

22.1yr (mean 12.11, SO = 3.98). This calculation included only 1 of2 MZ twins in one

48

family, both ofwhich were otherwise taken as probands. The age at testing of7 probands

from the 7 clinically referred families ranged from 4.72 to 17.95yr (mean 8.51, SO =

4.88). Ages at testing of2 self-referred probands were 9.6 and 21.35yr. The male-female

ratios in these recruitment-based subgroups ofprobands were 13/1,6/1 and 2/0

respectively. None ofclinically diagnosed children bad a language disorder cbaracterized

by fluent communication with inappropriate use of language, also referred to as the

semantic-pragmatic syndrome (Rapin & Allen, 1983; Rapin, 1996). Many ofthe 3S

clinically diagnosed children had additional non-exclusionary anomalies, most ofwhich

were related to motor fonction (motor problems, axiallbody coordination, cerebral

dysfunction); also noted were a medicai record reference to attention deficit and/or

hyPeractivity (12 children), and a record ofcentral auditory processing deficits (3

children).

3.2. Case-Control Comparison ofLanguage Test Scores

Table 2 presents comparison of language test scores between SLI subjects and

controls individually matched for age and gender. Differences in particular tests or sub­

tests (Table 2) were consistent with previous case-control comparisons in these subjects

(Gopnik, 1999; Rose & Royle, 1999), except for the Pointing task in the French group

that did not show significant difference trom controls in the previous study, which was

not matched for age and gender (Rose & Rayle, 1999). The tests that showed significant

difference between cases and controls (Table 2) were selected for further analysis; when

only 1 sub-test and the overall test showed significant result, then only the sub-test was

49

Table 2

Age and Sex Matched Case-Control& Comparison ofTest Scores

p (Englishl p <Frenchl

Derivational Morphology'

Verb Tense Morphology'

Verb TenseMorphology (Real Wordsf

Verb Tense Morphology (Non-real Words)'

Grammaticality Judgement'

Grammatica1ity Judgement (Grammatical Sentences)

Grammaticality ludgement (Ungrammatical Sentences)

Grammaticality Judgement (Correct Judgement)

GrammaticaIity Judgement (Correct Correction)'

Syntaetic Comprehension'

Syntactic Comprehension (Canonical Sentences)

Syntaetic Comprehension (Non-canonical Sentences)'

WUG Test (Real Words)

WUG Test (Non-real Wordsf

Pointing'C

Listening Comprehension

0.025 0.020

0.013 0.015

0.018 0.027

0.037 0.034

0.035 0.011

0.018 0.017

0.068 not scored

0.028 not scored

0.027 0.027

lb 0.180

0.018 0.027

0.043 not tested

0.066 not tested

0.042 not tested

0.157 0.026

0.48 not tested

'p < O.OS, Wilcoxon Signed Ranks test, 2-tailed. --rhere were 9 case control pairs in the French group (8male, 1 female) and 9 pairs in the English group (5 male, 4 female), except for the WUG test and WUG sub­tests in the latter group with 8 pairs (5 male, 3 female). Cases were SLI subjects meeting study criteria. Theage and sex matched controls were extemal contrais (8 in the English and 3 in the French group) or subjeetsunaffected as per family history report (l in the English and 6 in the French group). In the English group,ages ofall subjeets ranged trom 9.6Oyr to 22.1Oyr with maximal ditrerenœ of 1.54yrbetween the case andmatched control and the mean differenœ ofO.017yr; in the French group corresponding figures were 9.5Syr,2l.35yr, l.42yr and .024yr. b l , equal ranks, not significant. .:pointing was significant ooly in the Frenchgroup.

50

entered into the analysis. Ofthe entire test battery, only the Verb Tense Morphology test

showed significant differentiation from controls for both the overall test and ail sub-tests,

(Real Words and Non...real Words), across both language groups (Table 2). In this case,

based on the distinct theoretical foundation ofthese sub-tests as descnbed in the present

methods section (see alsoGop~ 1999; Rose &. Doyle, 1999) we analyzed further only

the sub-test scores, as per our goal to identify specifie components of linguistic

perfonnance which show familial resemblance. The 7 scores analyzed further in the

English group were Derivational Morphology, Verb Tense Morphology (Real Words),

Verb Tense Morphology (Non...real Words), Grammaticality Judgment (Ungrammatical

Sentences), Grammaticality Judgment (Correct Correction), Syntactic Comprehension

(Non-canonical Sentences), and WUG Test (Non...real Words). The 6 scores analyzed

further in the French group were Derivational Morphology, Verb Tense Morphology

(Real Words), Verb Tense Morphology (Non-real Words), Grammaticality Judgment

(Ungrammatical Sentences), Syntactic Comprehension (Non-canonical Sentences), and

Pointing.

3.3. Corre/ational Structure olTest Batteries and Relationship with Age and Gender

Tables 3 and 4 show, within the English and the French batteries respectively,

correlations between language test scores and correlations of test scores with age at

testing. In both languages, an ofthe test scores targeting specific theoretically derived

components ofPerfonnance were panly correlated among each other, exeept for the

WOG Test (Non-real Words) and Grammaticality Judgment (Correct Correction) in the

51

Table 3

Test and Age at Testing Correlations in the English Test Groupa

Test' DM VTMR VTMNR GJUNGR OJCC SCNC WUGNR.

DM

VTMR 0.60··

VTMNR

OJUNOR

GJCC

SCNC

WUGNR

0.44·· 0.59··

0.30· 0.44··

0.57"

0.31·. 0.20

Age Tested 0.44·· 0.22 0.16 0.15 0.13 0.14

•p < 0.05; iap < 0.01, Spearman's rho, 2-tailed. ~or the language tests, ail ofthe 55 tested subjects areanalyzed, except for the OJeC with 54 and WUGNR with 53 subjects. For the age at testin& 6 probandswere excluded and remaining 49 subjects were included, with 48 subjects for the osce and the WUGNRtest. bSymbols: DM, Derivational Morphology; VTMR, Verb Tense Morphology (Real Words); VTMNRVerb Tense Morphology (Non-real Words); OJUNGR, Grammaticality Judgement (UngrammaticalSentences); GICC, Grammaticality Judgement (Correct Correction); SCNC, Syntactic Comprehension (Non­canonical Sentences); WUGNR, WUO Test (Non-real Words).

52

•

Table 4

Test and Age al Testing Correlations in the French Test Groupa

Tesé DM VTMR VTMNR. GJUNR SCNe POINT

DM

VTMR 0.58··

VTMNR 0.60·· 0.67··

GJUNGR 0.63·· 0.73·· 0.64··

SCNC 0.42·· 0.39·· 0.3"· 0.44··

POINT 0.43" 0.47·· 0.38·· 0.43·· 0.39"

Age Tested 0.44·· 0.60·· 0.46·· 0.45" -0.01 0.38··

.p < 0.05; ••p < 0.01, Spearman's mo. 2-tailed. aAll ofthe 67 subjects are presentai, except for age at testÏDgwhere 12 probands were excluded and remaining 55 subjects were included. bSymbols: D~ DerivationalMorphology; VTMR, Verb Tense Morphology (Real Words); VTMNR. Vero Tense Morphology (Non-realWords); GJUNG~ Grammaticality Judgement (Ungrammatical Sentences); SCNC. SyntacticComprehension (Non-canonical Sentences); POINT. Pointing.

S3

English group. Derivational Morphology and Grammatical Judgment (Ungrammatical

Sentences) test scores were significantly correlated with age in the English group. In the

French group, most test scores showed similar and significant correlation with age except

for the Syntactic Comprehension (Non-Canonical Sentences). Gender comparisons for

age at testing and test scores, excluding probands, were made between 31 males and 24

females in the French test group offamilies, and between 23 males and 26 females in the

English test group offamilies. The only significant gender ditTerence, within the power

limits of the sample sizes, was found for Derivational Morphology test in the French test

group, with males showing poorer performance (p = 0.028, two-tailed, Mann-Whitney U

test).

3.4. Sib/ing Resemblance for Specifie Components ofLinguistic Competence

As described in the methods section, in the English group 41 sibling pairs from

the densely affected extended FE pedigree were analyzed. In the French group, 38 sibling

pairs from 10 families were analyzed, with 15 pairs from the single nuclear family.

Table 5 presents correlations for language test scores in sibling pairs from the

English test FE pedigree, and the French test group ofpedigrees. In the FE pedigree,

performance on the Derivational Morphology test showed significant sibling correlation.

In the French test group ofpedigrees, performance on the Verb Tense Morphology (Real

Words), as weil as the Verb Tense Morphology (Non-real Words), showed significant

sibling correlation. In order to examine whether a correlation between age at testing in

sibling pairs might potentially account for observed significant correlations in language

S4

Table 5

Siblinga Correlations for Specifie Components ofLinguistie Competence

French Pedigrees

Test English FE Pedigree lN =10)

~ If Il Nœm ~ Il

Derivational Morphology 41 0.52" 0.001 38 0.27 0.10

Verb Tense Morphology (Real Words) 41 -0.02 0.90 38 0.39· 0.02

Verb Tense Morphology (Non-reaI Words) 41 0.24 0.14 38 0.35· 0.03

Grammaticality Iudgement

(Ungrammatica1 Sentences) 41 0.06 0.72 38 0.21 0.21

Grammaticality Iudgement

(Correct Correction)b 41 -0.16 0.31

Syntactîc Comprehension

(Non-canonica1 Sentences) 41 -0.04 0.80 38 0.19 0.25

WUG Test (Non-reai Wordst 36 0.02 0.92

Pointingd 38 -0.04 0.80

'p < 0.05; "p < 0.01, 2-tailed, Spearman's ma coefficient ofcorrelation (r,). anere were 10 male and 12female pairs in the English speaking FE pedigree, and 21 male and 4 fema1e pairs in the French group of 10pedigrees. Remaining sibling pairs were ofdifferent sexes. ~ot scored in the French language group.eAdnûnistered only in the English language. dpointing is not aoalyzed in the English language because it didnot differentiate cases from controls.

55

test scores, we computed partial correlations controlling for age at testing (Table 6). The

sibling correlation for performance on the Verb Tense Morphology (Real Words) in the

French language group remained significant ailer controlling for age. The sibling

correlation for performance on the Derivational Morphology test in the English FE

pedigree remained substantial after controlling for age, although with borderline

statistical significance (p = 0.05), perbaps due to power limitations.

56

Table 6

Partial Sibling Correlations Controlling for Age at Testing

Lanauaae ]§ ~ r R ~.LI!IIIIIIJ

English

FE Pedigree Derivational Morphology 3S 0.3ge

0.02 034 005

Frencb

Pedigrees Verb Tense Morpbology (Real Words) 34 0.42e

0.01 0."- 001

(N = 10) Verb Tense Morphology (Non-real Words) 34 0.40e

0.02 0:7 o 14

•P < 0.05; liP< 0.0l, 2-tailecL df=N - 2 for Pearson's rand df= N - 4 for panial correlation ·Pan.alcorrelations, controUing for Slbling correlations for age al testing, were computed using normal Z scores inmore numerous SlDling pairs from the age group younger than 2Syr at testing.

57

4. Discussion

We examined specifie theoretically derived components ofperformance on the

English or French Linguistie Test Profile Battery in families ofSLI children, recruited

ftom various sources within each language group, and most ofwhich were known to bave

al least one impaired first-degree relative. The examined test scores differentiated SLI

cases from age and sex matched controls, and were general1y partIy correlated.

Significant sibling correlations were found for performance on tests that involve

production ofgrammatical morphology. These include Derivational Morphology in the

English language (N =41 sibling pairs from the single densely affected FE pedigree), and

Verb Tense Morphology (Real Words) as weil as Verb Tense Morphology (Non-real

Words) in the French language group (N = 38 sibling pairs from 10 pedigrees). The

observed correlation oftest scores with age may be related, in part, to therapeutic effects

and the use of leamed strategies for compensation of language impainnent (paradis &

Gopnik, 1997; Kehayia, 1994; Kehayia., 1997). Sibling correlation for Verb Tense

Morphology (Real Words) in the French group remained significant after controlling for

age. The sibling correlation for Derivational Morphology in the English speaking FE

pedigree was borderline (p =0.05) after controlling for age.

Independent studies demonstrate that impaired grammatical morphology is a

predominant aspect ofSL!, notwithstanding the lack ofconsensus regarding particular

etiological hypotheses (Rice & Oetting, 1993; Rice & Wexler, 1996; Oetting & Horohov,

1997; Leonard et al. 1999; Riee, 1999). A series ofGLIP reports based on the analysis of

English and French speaking subjects from the present study, as well as Greek and

58

Japanese speakers, advanced a cross-linguistic hypothesis of impaired ability ta construet

morphological rules in SLI (summarized inGo~ 1999; Rose &. Doyle, 1999). Within a

somewhat different grammatical account, a set ofgrammatical morphemes for Tense

marking (-s third persan singular, -ed regular past, BE, and 00) was proposed as a

clinical marker for English sPeaking SLI children (Rice &. Wexler, 1996; Bedore &.

Leonard, 1998).

The present study provides no information that could distinguish between the

relative contributions ofgenetic and environmental factors to observed sibling

resemblance. A recent twin study reported heritability of0.45 for extreme, composite

English language scores where at least one twin bad poor oral language status without

other developmental or sensory impairments; sunilar results were obtained when the

required minimal nonverbal IQ was either 70 or 85 points (Tomblin &. Buckwalter,

1998). The composite language score in the Tomblin study comprised 4 receptive and 4

expressive test measures often used in clinical praetice. Neither the composite language

score nor individual tests targeted Derivational Morphology or Verb Tense Morphology

as specifically as tests examined in the present report. Another English language twin

study ofSLI (Bishop et al. 1995) reported high heritability estimates for Word Finding,

for a Test for Reception ofGrammar, and for the Comprehension test from the WISC-R

intelligence test. A lower heritability was reported for Repeating Sentences, suggesting

that sorne specifie aspects of linguistic competence could he onder greater genetic

influence then others. Again, none ofthese tests specifically targeted Derivational

Morphology or Verb Tense Morphology. The hypothesis ofsubstantial heritability for

59

these particular components ofthe SLI phenotype awaits further specifica1ly targeted

studies.

4./. Pedigree Structure for Sihling Pairs in the English and French Test

AlI sibling pairs tested in English originate from the single extended FE pedigree

which is densely atTected Ce.g. 14/34 atTected cousins) and therefore not representative of

SLI pedigrees. A high proportion ofatTected relatives is the reason that this particular

pedigree was selected for extensive testing, and this could also he positively related to

willingness to participate in the project. These circumstances might have a priori reduced

the generalizability offindings to the larger SLI population. This might potentially relate

to the lack ofsibliog resemblance for Verb Tense Morphology, proposed to he a clinical

marker for English speaking SLI children (Riec & Wexler, 1996). The proband in the FE

kindred had a recorded nonverballQ of71, and evidence ofa central auditory processing

defieit, with normal audiogram as per SLI criteria in this study. Regarding the density of

impaired individuals and nonverbal IQ, the FE pedigree is similar to the K family where a

fully penetrant autosomal dominant gene was mapped to severe speechllanguage

impairment with speech and orofacial dyspraxia (Vargha-Khadem et al. 1995; Fisher et

al. 1998). However, the FE pedigree does not show the same Mendelian pattern of

inheritance or orofacial dyspraxia in affected memhers. It might he hypothesized that

pedigrees which segregate larger numher ofspecifie risk factors, i.e. defieits in nonverbal

IQ, auditory processing, etc., are more Iikely ta he densely affected, but this hypothesis

requires more research ioto the effects ofparticular factors.

60

In contrast, sibling pairs tram the French group in the present study originate from

10 pedigrees, none ofwhich were denselyatTected. The differences in both the test

language and pedigree structures make it difficult to interpret the observed ditTerences in

sibling correlations between the English and French test subjects. Tbese familial

considerations may underscore the etiological complexity ofimpaired grammar which is

on the surface rather similar aeross languages and pedigree structures (including the FE

and the K families), featuring a prominent deficit in morphological produetîon (Gopnik,

1999).

4.2. Limitations

The test-retest reliability ofadministered language tests is not known. It is aIso

clear that the present study was underpowered, and is thus wlnerable to both Type 1and

Type II statistical errors. The smalt sample size also precluded stratification ofsibling

pairs by gender. It is not known whether the assumption ofan interval scale of

measurement for language test scores, which underlies the computation ofpartial

correlations controlting for age at testing, is valid. The exclusionary nonverbal IQ

criterion was 70., rather than 85 points as suggested in sorne ofthe Iiterature. However.,

reeent views (Gopnik & Goad, 1997; Plante, 1998; Tager-Flusberg & Cooper, 1999)

conceptuaIize a nonverbal IQ between 70 and 85 as a potential risk factor, rather than

exclusionary condition for SLI.

61

4.3. Conclusion

We approacbed familial study ofgrammati~impainnent in SLI from the

perspective ofa complex phenotype with theoretica11y distinct components which may he

partially decomposed by test design and statistical analysis. The results, which require

independent replication, suggest that Derivational Morphology and Verb Tense

Morphology production, independently documented as predominant aspects ofSLL

warrant particular attention in future familial and genetie studies of this important

communication disorder. More sensitive measurements, sueh as psychometrie on-line

task-processing time (Kebayia, 1994; Kehayia, 1997) could he developed to deteet

impaired adults who may score at high levels on the present test battery due to correlation

with age. Analogous to the example ofdyslexia, these specifie components ofthe SLI

phenotype could potentially he useful for geoetic studies, perhaps eventually providing

molecular elues to underlying influences of infonnation processing, linguistic neural

substrates or other etiological processes that are oot weil understood at present.

62

Aeknowledgement

This work within the multidisciplinary MeGill University Genetic Language

Impainnent Projeet (MyrnaGo~ PI) was supported in part by an Intercouneil Group

Grant from the Medical Researeh Couneil ofCanada and the Social Sciences and

Humanities Researeh Couneil (M. Gop~Principal Investigator). Additional support

from the Medical Researeh Couneil (MA...11663 t GR...14501) is aclmowledged. This work

is in partial fulfillment ofthe requirements ofthe Ph.D. degree (Ilija Kovac).

63

•

AppeDdix

Analyzed Subjectg& by Test Language and Familial Relationships

Test Language

Family

~ ~

Family Members Family Members

Nuclear ~ ~rd Other Nuclear ~Dd tJ:lrd Other

AI - - - - 4 - - -AR - - - - 5 - - -BC - - - - 2 - - -CA - - - - 4 - - -CG - - - - S - - -CT - - - - 5 - - -CX - - - - 4 - - -DP - - - - 4 1 2 -DS - - - - 4 2 2 le:

EA - - - - 8 - - -FE 3 4 14 - 3 1 3 r:FG 1 - - - 1 - - -FX - - - - 2 - - -LB 4 1 3 ICI - - ICI

SB 2 - - - 2 - - -DA 1 - - - - - - -HA 4 - - - - - - -HB 3 1 - - - - - -

He 1 - 1 - - - - -lA 3 - - - - - - -JO 3 - - - - - - -LA 1 - - - - - - -SA 4 - - - - - - -I: 30 6 18 1 S3 4 7 3

~cluded subjects not shawn, (N = 16 and 12 in the English and French test group respectively, as notOO inthe methods section).~ee ofrelationship ta the proban~ who is included here among nuclear familymembers. ~arried-in. ~ounh-degree relative.

64

Bridging CommeDtary

Like the preceding one, the following manuscript, entitled "Attention

Defieit/Hyperaetivity in SLI Children Inereases Risk ofSpeecblLanguage Disorders in

First Degree Relatives: A Preliminary Report"t is based on the data gathered within the

McGill University Genetie Language Impairment projeet (Myrna Gopnik, PI). However~

this report is based on Medical records offamilies identified through the Association of

Quebec Dysphasie Children, without regard ta familial aggregation ofthe disorder. This

design allows for a different approaeh to potentially defining a more familial form ofthe

SLI phenotype, by examining the influence ofattention deficit/hyperactivity in SLI

children on familial aggregation ofspeecbllanguage disorders. Among 27 anal~ozed

families, 8 families also completed language test battery in the course of research

analyzed in the preceding manuscript. In these 8 families, 4 adults who were reponedly

impaired achieved test scores similar to contrais; however, this does not invalidate family

history information because these adults might have compensated for potential language

impainnent. Remaining test scores in these 8 families were unremarkable with respect to

family history information. Because Most offamilies analyzed in the following repon

were not tested on the language test batteryt it is not possible to evaluate the relallonshlp

between findings from these two manuscripts.

65

2(b). AITENTION DEFICITIRYPERACTIVITY IN SU CllILDREN INCREASES

RISK OF SPEECBlLANGUAGE DISORDERS IN FlRST-FEGREE RELATIVES:

A PRELIMINARY REPORT

The present chapter consists ofthe following manuscript in submission, entitled

as above.

66

Increased Risk

Running head: INCREASED FAMILIAL RISK IN SU

Attention Deficit/Hyperactivity in SLI Children Increases Risk ofSpeech/Language

Disorders in First-Degree Relatives: A PreJiminary Report

llija Kovac1, Berdj Garabedian2

, Christele Du Souich2,4, Roberta M. Palmourl,2.3

Departments ofBiologyl, Human Genetics2 and Psychianyl, McGill University,

Montreal, Québec~ CANADA

4Present address: Department ofMedical Genetics3, University ofBritish Columbi~

Vancouver, British Columbia, CANADA

Address for correspondence:

Roberta M. Palmour, Ph.O.

Department ofPsychiatry, McGill University

1033 Pine Avenue West., Room 307

Montréal, Québec, H3A lAI

CANADA

Tel. (514) 398-7303

Fax (514) 398-4370

E-mail: mc23@musica.mcgill.ca

67

Increased Risk

Abstraet

Specific language impainnen~ or developmental dysphasia, denotes the inability

to acquire normal expression and/or comprehension of language in the absence of

peripheral hearing impairmen~ neurological disorder, and mental retardation. The

presence ofattention deficit/hyperactivity in sorne SLI children has previously been

documented. This family history study used 27 SLI families, identified through the

parents from the dysphasia association, to examine the relationship between anention

deficit/hyperactivity in SLI children and the risk to first-degree relatives. Ail SLI chlldren

were clinically diagnosed with speech/language disorder; Medical records were scarched

for the presence ofany ofthe exclusion criteria noted above. Higher odds of

speech/language disorders were observed in first-degree relatives of 13 SLI children \\1th

Medical record ofattention deficitlhyperactivity, than in relatives of 14 SLI chlidren

without such record (15/27 and 4/46 respectively, p=O.OOI). This preliminary repon

warrants additional study to investigate the relationship between speech/language

disorders and attention deficitlhyperactivity in families of SL! children.

Educationa/ Objectives: The reader ofthis article will: 1) leam about the definltlon.

prevalence and cornplexity ofthe SLI phenotype 2) learn about the relation bc:tween co­

morbid attention-deficit/hyperactivity in SLI children and the risk of speech.language

disorder in their relatives.

68

Increased Risk

KEY WORDS: communication disorder~ attention deficit, hyperactivity, phenotype,

familial

Introduction

Specifie language impainnent (SLI), or developmental dysphasia, denotes the

inability to acquire correct expression and/or comprehension oflanguage and is usually

diagnosed at preschool or early school age. The diagnosis ofSLI requires bath positive

identification ofspeech/language impairment, as weil as exclusionary and/or discrepancy

criteria comparing speech-language ability to some other cognitive measure (Aram,

Morris, & Hall, 1993; Dunn et aL 1996; Plante, 1998). Exclusion criteria commonly

include mental retardation, peripheral hearing impairment and overt neurological

disorder; operational measures of these parameters vary from parental/clinician's

descriptions to formai evaluations (Lahey & Edwards, 1995; Lewis, Ekelman, & Aram,

1989; Lewis, Cox, & Byard, 1993; Neils & Aram, 1986; Redmond & Rice, 1998; Rice,

Haney, & WexIer, 1998; Tallai, Ross, & Curtis, 1989; Tomblin, 1989; Tomblin et al.

1997). Children diagnosed with SLI in accordance with these exclusion criteria often

have milder behavioral, neurological, auditory and cognitive deficits (Goorhuis-Brouwer

& Wijnberg-Williams, 1996; Lubert, 1981; Powell & Bishop, 1992; Redmond & Rice,

1998; TallaI et al. 1991; Wright et al. 1997). Positive operational criteria for

speech/language impairment also vary among studies, but a commonality is that probands

are generally impaired enough to warrant clinical treatment. The best estimate ofthe

population prevalence (USA) for SLI is 7.4% in preschool children (Tomblin et al. 1997).

69

•

Increased Risk

The familial aggregation ofSLI bas been repeatedly documented, and twin data suggest

that genetic factors May he etiological (Bishop, North, &. DonIan, 1995; Lewis, Ekehnan,

&. Aram, 1989; Neils &, Aram, 1986; Rice, Haney, &, Wexler 1998; Tallai, Ross, &

Curtis, 1989; Tomblin. 1989).

Attention deficit/hyperactivity behavioral problems are observed in SLI children

(Aram, Ekelm~ &, Nation, 1984; Goorhuis-Brouwer &. Wijnberg-Williams, 1996;

Redmond and Riee, 1998; Tallai et al. 1991), raising the question ofthe relationship

between attention deficitlhyperactivity disorder (ADHD) and SLI. ADHD is another

eommon childhood onset disorder with a population prevalence of3·10% (Cantwell,

1996), and substantial evidence of familial aggregation with genetie etiological factors

(reviewed in Rutter et al. 1999). According to the OSM-IV criteria, sorne individuals May

predominantly show either attention deficit or hyperactivity, but MOst show a combined

ADHD phenotype (APA, 1994). There cao be developmental transition between these

symptoms. Co-morbidity between ADHD and other psychiatrie disorders is weil

documented (pliszka, 1998), and perhaps 2/3 ofchildren with ADHD show speech and

language disorders (Cantwell, 1996; Love & Thompson, 1988; Smalley, 1997).

Conversely, children with speech/language problems, but undefined with respect to the

exelusionary SLI criteria, show co-morbidity with other psychiatrie disorders, including

ADHD (Beitchman et al. 1986).

The rationale for the present study is that a comprehensive description ofthe

phenotype in individuals with a panicular complex disorder May allow discrimination of

clinical subtypes, which May in turn improve the power to identify etiological factors or

processes. A useful component in validating potential etiological subtypes is an

70

•Increased Risk

investigation ofthe familiality of the different phenotypes. Labey and Edwards (1995),

following this rationale, reported an increased risk to relatives ofSU children with

expressive, as compared to SLI children with mixed expressive-receptive language

disorder. Tallai and coworkers (TallaI et al. 1991) found tbat SLI children who had at

least one impaired parent had more attention/hyperactivity behavioral problems as rated

by parents and teachers. In view ofthe latter result, it cao he hypothesized that the risk to

relatives ofSLI children with attention/hyperaetivity behavioral problems might he higher

than the risk to relatives ofSLI children without such problems. In this study we

compared the risk to first-degree relatives in subgroups ofSLI children ditTerentiated by

the presence or absence ofthe Medical record ofattention deficitlhyperactivity.

Method

Participants

Recruitment. French speaking families with speech/language impaired children

were initially approached for the McGill University Genetic Language ImPainnent

Project (Myrna Gopnik, Ph.D., PI) by announcement in the newsletter of the Association

ofQuebec Dysphasie Children (AQEA). Infonnants from the total of 156 responding

families were contacted by telephone (Figure 1) to canfion their interest in participating

in the projec!, and family history infonnation (described in detail below) was obtained.

Upon consent, a systematic review ofthe clinical records of language impaired children

was conducted. The hospital and/or school records for speech/language imPaired children

from 76 families were available (Figure 1). Participants were treated in accordance with

71

Increased Risk

Telephone Interview

(N= 156)

No Medical

RecordsMedical Records Review

(N =80, excluded)(N=76)

SLI(N=27)

SLIadlh)'P- (N = 14)

SLIadlhyp+ (N = 13)

~on-SLI (N =24, excluded)

bundefined (N = 25, excluded)

Figure 1. Selection and Subgrouping ofSLI Families. Symbols: N, number offamilies~

SLIadlh~'P-' no medical record ofattention deficitlhyperactivity in the SLI proband;

SLIadlhyp+. Medical record ofattention deficit/hyperactivity found in the SLI proband.

aNon-SLI families are those in which Medical records documented exclusionary

condition(s) in the speech/language impaired children. tundefined families are those in

which medical records did not contain ail information pertinent to exclusionary criteria.

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Increased Risk

the "Ethical Principles ofPsychologists and Code ofConduct" (American Psychological

Association, 1992).

Inclusion and exclusion criteria The inclusion criterion in the present study was

the diagnosis ofspeecbllanguage disorder by a certified speecbllanguage pathologist. By

virtue ofAQEA membership, ail families had speecb/language-impaired children who

met this criterion. The presence ofone SLI proband in the family was sufficient for

inclusion ofthe family in the study, regardless ofthe status ofother speech/language­

impaired children, ifany, in the same family. Exclusion criteria in the present study were:

(1) no peripheral hearing impairment, as per Medical record ofa formal audiological test

such as audiogram or tympanogram, depending on examining physician, or the

improvised audiological exam (2 probands); (2) no mental retardation, as per medical

record ofa nonverbal or perfonnance IQ score ~85, formai psychological testing, or

clinical psychological reports; (3) no overt neurological disorder, as per Medical records

ofa neurological exam and/or EEG, MRI or CT scan; and (4) no developmental

syndromes or serious medical conditions (one child had a coloboma and was excluded).

Retention ofSLI families. Speechllanguage impaired children whose Medical

records did not contain sufficient information pertaining to exclusionary criteria were

classified as "undefinedn and excluded from the present study, as were the children

whose medical records documented exclusionary conditions (Figure 1). The 27 families

with speecManguage impaired children whose medical records documented absences of

exclusionary conditions were retained as SLI families (Figure 1).

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Increased Risk

Family Historv

Family bistory interview. A semi-struetured family history (FH) interview

(questionnaire in the Appendix), with infonnants who responded to the recruiting

announcemen~ was conducted over the telephone by a trained genetie counselor.

Information on sex, birth date, degree ofrelation, general health (medical problems,

mental retardation, hearing, or psychological problems), speechllanguage problems,

speech therapy, readiog/writing problems and educationaVschool problems was collected

Family history information pertaining to first, second and third degree relatives of

speeeh/language impaired children was obtained Most ofthe infannants from the initial

156 families, and all informants in the 27 SLI farnilies presented in this report (Figure 1),

were mothers.

Family history based classification of relatives. Here we initially use phenotype

definition similar ta that used by Tallai and coworkers (Tallai et al. 1991). Family

members were classified as affeeted if they have a present or past report of

speechllanguage problem, reading/writing problem, received speech therapy, and/or

oogoing educational or school problems. We have also used an alternative phenotype

definition, where individuals with reported ooly learning or ooly readingl writing problem

are classified as unaffected. This alternative definition was used exclusively in the event

of initially significant difference in the risk ta relatives between SLI subgroups, to assess

whether this difference persists when the affected phenotype is restricted to those reports

that refer specifically ta the speech/language problem. Relatives younger than 3yr were

excluded from the analysis ofFH da~ because speech/language impairment May not be

reliably observed at younger ages.

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Statistical Analysis

The Pearson's X2 test was used to test the hypothesis that the odds ratio for having

an atfeeted first-degree relative, calculated for the subgroups ofSLI probands in 2 x 2

contingency tables, is significantly different ftom 1 (Fleiss, 1981). When any ofexpeeted

cell counts was ~5, the Fisher's exact test was used The tests and odds ratio estimates

were performed using the SPSS 8.0 statistical software. Statistical significance in this

report was generally determined at the 0.05 level in 2..tailed tests.

Results

As described in the Recruitment section, the selection ofSLI families was a

multistage process incorporating a number offactors, such as family membership in

AQEA, awareness of recruiting announcement, participation in family history interview,

and completed review ofMedical records. While we do not have enough information to

examine potential biases with respect to the sampling offamilies at most stages, we have

compared 76 families in which the Medical records ofspeech/language impaired children

could be reviewed with 80 families for which only the family history interview was

completed (Figure 1). These two groups were not significantly different with respect to

the proportion ofaffected first-degree relatives [0.16 or 42/261, and 0.21 or 58/282

respectively, ('x.2 = 1.81, P=0.18, 2-tailed)]. The groups were also similar in the

male/female ratio ofclinically diagnosed speech/language...impaired children (3.1: 1or

65/21 and 3.7:1 or 70/19 respectively). In order to examine whether the absence of

pertinent data in the Medical records might bias the retention of SLI families, we

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compared the "undefined" families~ excluded due to the lack ofda~ to the pooled

uexcluded'" (due to exclusionary conditions) and SLI groups (Figure 1). There were no

significant ditTerences~ with proportions ofaffected first-degree relatives of0.15 (12179)

vs. 0.17 (30/182), respectively, and malelfemale ratios ofclinically diagnosed children of

3.1:1 (22/7) vs. 3.1:1 (43114). Hence the stratification associated with availability and

completeness ofmedical record information did not appear to have introduced bias, at

least with respect to familial incidence and sex ratio~ ioto the pool of families

investigated further.

The SLI families

ln 27 SLI families (Figure 1), identified as described in the method section, there

were 28 SLI probands among 32 clinically diagnosed speechllanguage impaired children.

ln one family, there were male twin (purportedly MZ) SLI probands, and in 3 other

families there were clinically diagnosed speechllanguage impaired children in addition to

the SLI proband. The Mean age of SLI probands in these 27 SLI families (excluding 1 MZ

twin proband) was 8.10 ± .75 years, ranging from 3-18 years. The male-female ratio of

SLI probands was 23:4 (not counting one reportedly MZ male twin)~ and 25:6 when aH

clinically diagnosed speechllanguage impaired children are considered.

Of the 28 SLI probands, 22 (79%) had Medical records evidence of non­

exclusionary anomalies such as mild neurological symptoms (fine motor problems,

coordinationlbalance problems, immaturity, motor delay, minimal cerebral dysfunction,

slight hypotonia) and/or behavioral problems (attention deficitlhyperactivity, mild autistic

signs~ unspecified behavioral problems). The fact that we required ail probands to have a

neurologjcal evaluation in Medical records probably contributed to the identification of

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mild neurological signs, which could he under-reported ifonly the report ofa parent or

speech pathologist was used. AIl ofthe S SU probands with Medical record references to

mild autistic signs were diagnosed with semantic-pragmatic syndrome, which often

appears to he similar to the communication ofautistic children (Rapin & Allen, 1983);

i.e., these children may speak about themselves in the third persan. No SLI probands in

our study were diagnosed with sensory...motor disorder ofSPeech production (dysarthrîa),

although some investigators think ofverbal dyspraxia (diagnosed in some children) as a

severe speech production disorder rather than a language disorder, dePending on

unresolved models of language reception/production (Rapin, 1996).

Clinical Subgroups

The 13 families in which Medical records for 14 SLI probands (including 2 twins)

contained any reference to attention deficit and/or hyperactivity (not necessarily a DSM

diagnosis) in psychological or neurological evaluations, referred ta hereafter as the

medical record ofattention deficit/hyperaetivity (ad/hyp), constituted the SLladlhyp+

subgroup (Figure 1). The remaining 14 families, with no Medical record ofattention

deficitlhyperactivity in the SLI proband, constituted the SLIadJbyp- subgroup (Figure 1).

The difference in ages of 13 SLI probands from the SLladlhyp+ subgroup and 14 SLI

probands from the SLladJhyp- subgroup did not reach statistical significance (9.58 ± 1.14

vs. 6.71 ± .87 years respectively, p = 0.06, t-test, 2-tailed), however this small sample had

little statistical power. One ofthe 2 MZ twin SLI probands from the SLladIhyp- subgroup

was excluded from this age comparison because his age is correlated with the age ofbis

twin SLI brother, confounding the comparison. The male-fernale ratios of SLI probands

in the SLladlbyp+ subgroup and SLIadlbyp'" subgroup were 12:1 and Il:3, respectively. We

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Increased Risk

note that the reportedly MZ twin SU probands were together in the SLIadlhyp+category,

a1though one was diagnosed with syntactic-phonological syndrome and verbal dyspraxia,

while the other was diagnosed with syntactic-phonological syndrome alone (diagnostic

definitions given further, below).

Family Historv in Clinical Subgroups

Table 1presents family history information for first-degree relatives ofthe

SLladlhyp- and SLladlhyp+ subgroup, where subgroups are defined respectively by the

absence or presence ofthe Medical record ofattention deficit/hyperaetivity as described

above. In addition, exclusively in the SLladlhyp+ subgroup we found 4 clinicaUy diagnosed,

speech/language impaired siblings ofSLI probands from 3 families. Together with Il

relatives affected by FR criteria (Table 1), these 4 children malee a total of 15 affected

first-degree relatives in the SLIadIbyp+ subgroup, as compared to 4 affected first-degree

relatives in the SLladIbyp- subgroup.

Table 2 shows that SL! probands with a Medical record ofattention

deficit/hyperactivity have higher odds ofhaving an affected first-degree relative then SLI

probands without a record ofad/hyp. Due to the moderate sample size, the estimate of the

odds-ratio value is imprecise as shown by a broad 95% confidence interval (Table 2).

Following this significant resul~ we have also tested the odds-ratio difference using an

alternative phenotypic definition, whereby 4 individuals with a report of isolated learning

or readinglwriting problems (Table 1) are classified as unaffected for speech/language

disorder. This alternative odds-ratio difference remained statistically significant [4/46 vs.

11/31 in the SLladlhyp- and SLladIhyp+ subgroup respectively (X2 = 5.54, df= 1, P=0.019,

Pearson's X2 test, 2-tailed; OR = 4.08, 95%CI = 1.19 - 13.98).

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Table 1

Family History Report for First-Degree Relatives

Family History Report

Language problem

Language and leaming problem

Expressive problem

Expressive and leaming problem

Learning problem

Pronunciation problem

Articulation problem

Stuttered when young

Reading and writing problem

1

1

1

1

3

.,-

Note. Symbols: aSLI probands without medical record ofattention deficit'hyperacu\'ny. N

= 50 first-degree relatives in 14 families; bSLI probands with medical record ofattention

deficit/hyperactivity, N = 42 first-degree relatives in 13 families. COashes denote absence

ofthe corresponding family history report in a given subgroup ofSLI children.

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Table 2

Classification ofFirst-Degree Relatives by Family Historv Report

Subgroup

4 46

Odds Ratio C95%Cn

dSLIadlhyp+ 15 27 6.39 (1.92 - 21.23) 10.7 1 0.001

Note. Symbols: aaffected; bunaffected; criteria for classification based on the

family history report are provided in the method section; cSLI probands without medical

record ofattention deficitlhyperactivity, N = 14 families; dSLI probands with medical

record ofattention deficitlhyperactivity, N = 13 families; epearson's X2 test, 2-tailed.

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Table 3 summarizes the proportions ofvarious classes ofaffected first-degree

relatives in the SLIadIhyp- and SLIadtbyp+ subgroups. We note that the reported proportions

ofaffected second-degree relatives in the SLIadJhyp-and SLladIhyp+subgroup were 0.03

(5/177) and 0.11 (19/166), respectively. The reported proportions ofaffeeted third-degree

relatives (first cousins) were 0.07 (13/197) and 0.08 (17/201), respectively. The FR report

for extended relatives is expeeted to he less reliable than for first-degree relatives, and

less sensitive in particular, thus underestimating the risk to these relatives (Andreassen et

al. 1977). It is also subject to the reporting bias where relatives tram the informant's

lineage (maternai relatives in the present study) are more often reported as affected, as is

generally observed in the present study.

There were 5/14 families in the SLIadIhyp- subgroup and 5/13 families in the

SLIadlhyp+ subgroup in which clinically treated, speechllanguage-impaired children were

first-bom. Because the presence ofa clinically diagnosed speech/language...impaired child

may confer closer scrutiny to subsequently barn childre~ such stratification by birth

arder, when present, could contribute to differences in the proportion ofaffected siblings.

Another factor POssibly contributing to increased risk to first-degree relatives might be

increased assortative mating. There were 1114 and 1/13 families with bath parents

affected in the SLIadlbyp- and SLIadlbyp+ subgroups, resPectively. This is inconsistent with

the notion that attention deficit/hyperactivity mediated increase in assonative mating for

communication disorders (possibly as an etiologically independent modifier that

increases severity) might explain observed difference. The male-ta-male transmissio~

reported in sorne nuclear families from the SLladlbyp+ subgroup, would argue against a

simple X-linked pattern ofgenetic inheritance in this subgroup.

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Table 3

Risk by Type ofFirst-Degree Relative

First-Degree Relative aSLIlIdIhyp- bSLIadJhyp+

Parents 4/28 (0.14) 9126 (0.35)

Fathers 2114 (0.14) 4c113 (0.31 )

Mothers 2/14 (0.14) Sc,d /13 (0.3QI

Siblings 0/22 6c/16 (0.38)

Brothers 0/14 3c/I0 (0.3)

Sisters 0/8 3/6 (0.5)

4150 (0.08) 15/42 (0.36)

Note. Truncated at the age 3yr (n = 3 siblings from each subgroup). The I\\,n SLI

proband in 1 family from the SLIadlhyp subgroup was not counted as the first--deb-rree

relative because he was reportedly a MZ twin. Symbols: aSLI probands without medlcal

record ofattention deficitlhyperactivity, N = 14 families; bSL1 probands ";th medlcal

record ofattention deficitlhYPeractivity, N = 13 families; cincludes 1 person "1th a

report of learning problem; dincludes 1 person with a report ofreading/writing problem.

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Heterogenous Speech/Language Phenotype in SLI Probands

Heterogeneity in the speech/language phenotype could potentially confound

observed SLladl11yp+ vs. SLIadIbyp- ditTerence in the risk to first-degree relatives. A clinical

diagnosis of semantic-pragmatic syndrome was round in the MediCal records of 8

probands. Other probands were diagnosed with semantic-pragmatic syndrome and

dyspraxia (2), syntactic-phonological syndrome (8), syntactic-phonological syndrome and

developmental verbal dyspraxia (8), syntactic and semantic deficit (1), or developmental

verbal dyspraxia (1). Semantic-pragmatic syndrome denotes correct phonology and

syntax accompanied by inappropriate use of language, indicating difficulties with

semantic and social aspects of language (Rapin & Allen, 1983; Rapin, 1996; Snow &

Swisher, 1996). Syntactic-phonological syndrome denotes poor phonology, syn~ and

morphology (Rapin & Allen, 1983; Rapin, 1996; Snow & Swisher, 1996). Verbal

dyspraxia denotes severe expressive language problem with sparse output and very poor

phonology (Rapin, 1996). We compared the odds ofhaving an affected first-degree

relative in the 8 SLI probands diagnosed with semantic-pragmatic sYndrome alone

("fluent" SLI, N = 3 probands in the SLIad/hyp+ subgroup), and the remaining 19 SLI

probands with documented problem in the domain ofsYntax-phonology r~non-fluenf'

SLI). The atTectedlunaffected ratio, including leaming and reading/writing problem as

affected, was 2/24 in the "fluent" vs. 17/49 in the "non-fluent" SLI subgroup (p = 0.08,

Fisher's exact test, 2-tailed; OR = 4.16, 95%CI = 0.89 - 19.51).

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Discussion

In this study we found significantly higher odds ofhaving an affected first-degree

relative in 13 families ofSL! probands with concomitant Medical evidence ofattention

deficitlhyperactivity in the proband, than in 14 families of SL! probands whose Medical

records showed no evidence ofattention deficit/hyperactivity. Tallai and coworkers

(Tallai et al. 1991) reported that family history positive SLI probands (defined as having

at least one affeeted parent) were more likely ta have attention/hyperaetivity behavioral

problems, as reported by parents and teachers on the Achenbach's Child Behavior

Checklist. The present study therefore extended this finding by providing independent

data on familial ris~ including parents and siblings, which shows that the converse

relationship May also hold true.

The phenotypic definition ofaffected first-degree relatives employed in the

present study was similar to that employed by Tallai and coworkers for the classification

ofaffected parents of SLI probands (TallaI et al. 1991), including a report of learning and

reading/writing problems in addition ta the speech/language problems. Due to the

association ofcommunication and learning disorders, MOst family studies ofSLI used

sorne fonn ofbroader phenotype definition based on FH information (Lahey & Edwards,

1995; Lewis, Ekelman, & Aram, 1989; Neils & Aram, 1986; Rice, Haney, & Wexler

1998; TallaI, Ross, & Curtis, 1989; Tomblin, 1989). In the present study we also

examined an alternative phenotypic definition, whereby individuals with a report of

isolated leaming problems or isolated reading/writing problems were classified as

unaffected The increased risk to first-degree relatives from the SLIadlbyp+ subgroup

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persisted under this alternative phenotypic definition, providing more confidence that the

observed diiferentiation May relate to speech/language disorders. Labeyand Edwards

(1995) did not find ditIerences in family history with respect to parent-reported

behavioral problems in SL! probands. However, few SL! probands in their study were

reported to have behavioral problems, and not ail ofthose were rePOl1ed as attention

related problems.

The present study is not informative with respect to the nature ofthe relationship

between speech/language disorders and attention deficitlhyperaetivity in famifies ofSLI

children. It could he speculated that attention deficitlhyperactivity, whether etiologically

independent or not, might hinder the improvement ofspeech/language performance over

time, facilitating the reporting ofspeech/language impaired individuals in the SLladIhyp+

subgroup. Language irnpaired individuals rnay use pragmatic eues and strategies, similar

to leaming ofthe second language, to improve their observable perfonnance over time

(paradis & Gopnik, 1997). Nevertheless, it remains a possibility that the SLladl1lyp+

phenotype may represent an etiological subtyPe of SLI, cbaracterized by familial factors

common to attention deficitlhyPeractivity and speechllanguage disorders. This

hypothetical commonality could relate attention defieit and SLI through information

processing, as TallaI and coworkers (TallaI et al. 1991) also reported differences in

nonverbal auditory attention and processing, in addition to attention/hyperactivity

behavioral problems, between family history positive and negative SLI probands. It bas

been suggested that infonnation-processing deficits can eontribute to language

impairment in sorne children (Curtiss & Tallai, 1991).

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The following limitations contribute to the preliminary character ofthis report.

Family history information is known to underestimate the rate ofaffected relatives

(Andreassen et al. 1977). First, our findings are based on the FH report on first-degree

relatives, which is generally more reliable than for extended relatives. Nonetheless, sorne

true cases might not have been reporte<!, and these cases might have been difTerentially

clustered in adlhyp negative families. Second, the presence or absence ofattention

deficitlhyperactivity in SLI children was based on the review ofMedical records

containing psychological and neurological evaluations, which is inferior to direct

examination. Thini, the consequence of increasing the stringency ofexclusionary criteria

by a requirement for pertinent medical record infonnation, which presumably improved

the reliability ofdiagnosis in SLI probands, was a reduction in sample size. The diagnosis

ofSLI was based on Medical records from difTerent clinicians with varying operational

measures, although major forms ofexclusionary conditions were absent in SLI children.

There was insufficient information to evaluate potential confounding effects ofage (the

SLIadlhyp+ probands tended to be older than the SLladlhyp- probands) or ofdifferent

speech/language phenotypes in SLI probands.

Conclusion

The present study, using 27 families identified through the parents from the

dysphasia association, provides preliminary evidence ofa higher risk ofspeech/language

disorders to first-degree relatives of SLI probands with attention deficit/hyperactivity

behavioral problems, than to first-degree relatives ofSLI probands without these

problems. Further study in a larger number offamilies, using direct assessment and

0Perational criteria for both speech/language disorders and attention deficitlhyperactivity

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Increased Risk

is needed to corroborate this finding, and to examine the relationship between SU and

attention deficitlhyperactivity. Potential benefits offurther research on this aspect ofSLI

May include improved intervention strategies for this important common disorder~ and an

increase in power for genetic mapping studies, given the hypothesis that SLI with

attention deficitlhyperactivity might prove to he a more homogenous etiological

subgroup. The power for genetic mapping would he increased by the potentially higher

population relative risk Â. [the risk to relatives ofa given degree ofrelationship divided by

the population prevalence (Risc~ 1990a; Risch, 1990b)] for the first-degree relatives in

the SLIadJhyp+ subgroup than in the SLladlhyp· subgroup.

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Increased Risk

AuthorNote

This work occurred within the multidisciplinary McGill University Genetic

Language Impairment Project (Myrna Gopni~PI) and was supported in part by an

Intercouncil Group Grant from the Medical Research Council ofCanada and the Social

Sciences and Humanities Research Council (M. Gopnik, Principal Investigator). Martha

Crago, Ph.D. and JoséeFo~ Ph.D. were co-investigators in the recruitment of families

described in this report. Additional support trom the Medical Research Council (MA­

11663, GR-14501) is acknowledged. This work is in partial fulfillment ofthe

requirements of the Ph.O. degree (llija Kovac).

88

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APPENDIX

Family History Questionnaire

Is (s)he generally healthy? (Any Medical problems, mental retardatio~ hearing, or

psychological problems?)

At what age did (5)he start talkinglspeak tirst words?

Did/does (s)he have problems sayinglpronouncing words?

Did/does (s)he have difficulty pronouncing sounds?/mixes up sounds?/changes sooods?

Didldoes (s)he make shorter sentences than other persons hislher age?

Did/does (s)he speak slowly (<SO wordslmin)?

Didldoes (s)he have difficulty finding the right word to express hislher ideas (uses words

such as 'stuff', 'thing')?

Did/does (s)he have problems with plurals and the past tense?

Did/does (s)he have reading or writing problems?

Did/does (s)he have problems in school (needs special tutor or special education)?

If yes, since what age and for how long?

Didldoes (s)he have difficuIty pronouncing long words (>3 syllables, e.g. )?

Didldoes (s)he mix up sounds or syllables in long words?

Didldoes (s)he receive speech therapy?

Ifyes, what type, for how long, and since what age?

89

Commentary

Here we recapitulate some important issues, noted previously, that may influence

the ÏDterpretation ofthe data collected in the McGill University Genetic Language

Impairment Project These issues relate to the method for diagnostic assessment ofSLI

children, and bilinguality, which is commonly observed in examined families.

The diagnosis ofSLI in probands was indirect, based on the review ofMedical

records obtained from various hospitals and/or schools. Medical records originated from

different clinicians, which have used ditTerent diagnostic instruments and practices.

Consequently, variation in the phenotype ofSU probands is likeJy to he increased. This is

not the case in Many other studies ofStI, which report direct examination ofSU

probands with the single set ofoperational instruments and criteria, although, as noted

previously, these instruments and criteria vary somewbat between different studies (Rice,

Haney, & WexIer, 1998; Tomblin et al. 1997). We cao not detennine how much ofan

effec~ ifany, this limitation might have on presented results. However, the requirement

for specifie Medical record information regarding major exclusionary criteria provides

some assurance that the children who were retained cao he classified as SLI children.

Bilingualism was common in families recruited for presented studies, whereas in

other SLI studies families are often required to he monolingual (Riec & Oetting, 1993;

Oetting & Horohov, 1997). In part due to lack ofresearch, currently there is Jack of

diagnostic norms for bilingual SLI children comparable to those for monolingual SLI

90

children. Besicles ofadding some uncertainty in Medical record diagnoses, tbis might

pose an issue ofits own ifwe were in a position to perfonn direct diagnostic assessment

ofSLI children. With regards to direct linguistic testing performed in the present study of

sibliDg resemblance for specifie test components, native French speakers administered

French test battery to primarily francophone families, and native English speakers

adrnioistered English test battery to primarily anglophone families (Gopnik, personal

communication). Therefore, variation in test performance that might bave been caused by

unequal matching ofexaminer's and subject language between two language groups is

prevented. More generally, there is evidence that bilingual context does not impede

language therapy, and provides the advantage ofbroader social adaptation (Bruck, 1982).

ft is therefore ofboth practical and theoretical interest to add emphasis to research on

bilingual children with language disorders. Particularly, in areas such as Quebec where

bilingualism is the rule it May he difficult to gather a reasonable sample of language

impaired children from monolingual families; more importantly, bilingual children with

language disorders must not he neglected in research efforts that May facilitate more

appropriate treatments.

91

3. PHENOTYPE DEFINITION IN ALCOHOUSM

3.1. THE DIAGNOSIS AND ETIOLOGY OF ALCOHOLISM

Diagnosis ofAlcoholism

Alcoholism is a common disorder with substantial negative effects on individuals

and the society (Merikangas, 1990) and is therefore a subject ofextensive research. The

term "alcoholism" is widely used by the general public to denote repeated drinking of

ethanol-containing beverages followed by disruptive effects on individual and social

functioning. The DSM-IV makes a distinction between the alcohol dependence and

alcohol abuse (APA, 1994). The alcohol dependence category is focused on alcohol­

seeking behavior, craving, tolerance and withdrawal. The alcohol abuse category is

focused on maladaptive alcohoI use manifested in adverse social consequences or

dangerous behaviors, i.e. driving while intoxicat~ without meeting the criteria for

diagnosis ofalcohol dependence. In addition ta DSM-IV, several other diagnostic systems

are used in recent alcoholism research, i.e. DSM-m-R, Feighner, ICD-IO (APA, 1987;

Feighner et al. 1992; WHO, 1992), resulting in partly concordant but partly discordant

diagnostic classifications (Schuckit et al. 1994). Calculation of the Iifetime prevalence of

alcoholism in the general population depends in part on the diagnostic system and

category, and estimates range from 5-14% in the United States (Kessler et al. 1994;

Myers et al., 1984; Robins et al., 1984). The National Comorbidity Study in the United

States reports lifetime general population prevalence ofDSM-m-R alcohol dependence

92

•

of 14.1%, with 20.1% in males and 8.2% in females (Kessler et al. 1994). Alcoholism is

comorbid with many other psychiatrie disorders, most notably antisocial personality

disorder and drug dependence, but also major depression, panic disorder, mania,

schizopbrenia (Heltzer" Pryzbeck, 1988; Kessler, 1997; Ross, 1995; Tomasson &

Vaglum, 1995).

Etiology ofAlcoholism

Family, adoption and twin studies suggest the importance ofboth genette and

enviromnental factors in the etiology ofalcoholism (reviewed in: Cotto~ 1979: Goldman~

1993; Merikangas, 1990; Prescott et al. 1994; Waldman & Slutske, 2000). Merikangas

(1990) reports, on average, a 7-fold increase in the risk to tirst-degree relatives of

alcoholic probands as compared to controls. While genetic influences in the nsL. for

alcoholism among women were initially not as clear as those for men (Preseau et al.

1994), more recent twin studies find evidence for substantial genetic influences on the

risk for alcoholism in women as well (Heath et al., 1997; Kendler et al., 1992) ThiS

could in part he related to the secular trend towards an increased frequency ofalcohollsm

in women (Reich et al. 1988; Stoltenberg et al. 1999), that might potentially contnbute to

increased expression ofvulnerability genes. In their review, Waldman and SIutsl~ (2000)

conclude that about 60% ofthe variation in risk ofalcoholism is due to genetlc

influences. Typical ofcomplex disorders, the mode of inheritance ofalcoholism 15 not

Mendelian.

Recent human and animal molecular genetic studies in alcoholism were reviewed

by Foroud and Li (1999). Genetic factors coosistently shown to influence alcoholism in

93

humans include polymorphisms in the ADH (alcahol dehydrogenase) and ALDH

(aldehyde dehydrogenase) genes, which are protective for alcoholism in Asian

populations. Most ofthe consumed alcohol is metabolized ta acetaldehyde, in part by

ADH, and the aceta1dehyde is then metabolized to acetate by ALDH The ALDH2*2

allele canfers a very low level ofaetivity ta the enzyme, and elevated levels of

acetaldehyde in carriers ofthis a11ele cause the aversive tlushing reaction whic~ at least

in some individuals, is a deterrent to excessive a1cohol consumption. Studies ofthe

ADH2*2 ailele also support the notion that this marker exerts a protective etTect (Foroud

& Li, 1999).

The implication ofADH and ALDH genes in alcoholism was facilitated by their

immediate funetional relationship to alcohol metabolism. This is not likely to he true for

most ofother susceptibility genes, whose effect may follow a more circuitous,

developmental pathway. Methodological advances in the genetic analysis ofcomplex

traits have facilitated numerous receot slodies. The most frequent analytical strategy by

far was the association study ofcandidate genes. The abstract search ofhuman studies in

the MEDLINE database (keywords "alcoholism" or "alcohol dependence" or "alcohol

abuse", and "gene") for the period January 1993-May 2000 identified 88 molecular

association studies using 28 candidate genes other than ADH or ALDH. Several, mostly

nonparametric linkage slodies ofcandidate genes were also identified in this search, sorne

ofwhich report association analyses as weil. Three studies from two whole genome scans

were identified (Foroud et al. 1998; Long et al. 1998; Reich et al. 1998). There is no

robust evidence identifying susceptibility loci for alcoholism, in contrast to the discussed

protective effects ofthe ADH and ALDH loci. The most promising candidate genes

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modulate neurotransmission and are involved in other psychopathology as weil, i.e.

serotonin S-HTIB receptor (Lappalainen et al. 1998), tryptopban hydroxylase, TPH

(Nie1sen et al. 1998), GABA receptors (Buck et al. 1997), and the dopamine receptor,

DRD2. Evidence for the implication ofthis last locus is highly controversial, perhaps in

part due 10 an etfect that is restrieted to particular subsets ofalcoholics (Hill et al. 1999;

Noble, 1998). Candidate genes, Many ofwhich are indicated by QTL mapping in animal

models, are reviewed in Crabbe et al. (1999) and Goate & Edenberg (1998).

3.2. PHENOTYPES JN MOLECULAR GENETIC STUDIES OF ALCOHOLISM

Similar to other complex disorders, and behavioral disorders in particular,

defining the phenotype precisely is important for the statistical identification ofgenetic

risk factors in alcoholism (Foroud & Li, 1999; Hill, 1998; Schork & Schork, 1998). For

this purpose, the generic approaches outlined in Chapter 1 are applied in a1eoholism

research as weil. Following are sorne examples that illustrate phenotypie aPPl'oaches to

genetie analysis in alcoholism.

The P300 eomponent ofthe event-related brain potential bas been targeted in

genetie studies as a lower order phenotype, more umoleeular" than a clinical diagnosis,

and implicated in vulnerability to alcoholism as well as comorbid psychiatrie conditions

(Begleiter &, Porjesz, 1999; Begleiter et al. 1998). Another lower arder phenotype in

alcoholism May he a reduced level of response to alcohol, which implicated the 5HTI

and GABAA alpha 6 genes in a recent pilot study (Schuckit et al. 1999). Severity is also

used to narrow the phenotype definition for genetic studies. There is some evidence that

9S

part ofthe controversy surrounding the intensely studied DRD2 gene MaY relate to the

greater mIe ofthis gene in severe alcoholism, and the failure ta take this into account in

some studies (Noble~ 1998). Severe alcoholism with withdrawal seizures or delirium

tremens was associated to DATI and SHIT gene (Sander et al. 1997a, Sander et aL,

1997), and alcoholism with delirium tremens was associated with the CCK gene

polymorphism (Okubo et al. 1999).

Subtypes ofAlcoholism in Molecular Genetic Studies

Regarding subtypes ofalcoholism, discussed in more detail in the section 3 3 ln

this chapter, molecular genetic studies are presently focused on the early onset. antisocial

form ofalcoholism (Hallikainen et al. 1999; Kono, 1997; Lappalainen et al. 19Qq.

Lappalainen et al. 1998; Nielsen et al. 1998; Parsi~ 1999; PesoDen et al. lQ98.

Samochowiec et al. 1999; Sander et al. 1998). The rationale for this strategy stems from

the extensive literature documenting higher heritability ofthis pbenotype~ discussed

further below. A significant part ofthis research is conducted using the sample based on

Finnish violent., early onset (Virkkunen &. Linnoila, 1997) alcoholic male cnmmal

offenders (Hallikainen et al. 1999; Lappalainen et al. 1999; Lappalainen et al 1998.

Nielsen et al. 1998; Pesonen et al. 1998). Lappalainen et al. (1998) defined antisocial

alcoholism as DSM-ill-R alcohol dependence or abuse with a concomitant diagnosis of

antisocial personality disorder or intermittent explosive disorder. In the same study"

linkage to antisocial alcoholism (defined by antisocial personality disorder and alcohol

dependencelabuse) was alsa evaluated in the population ofSouth American Indians. In

both populations, linkage ofthe serotonin receptor fITR lB gene to antisocial alcoholism

96

was observed; there was no linkage ofthis gene to either non-antisocial alcoholism or the

combination ofantisocial and non-antisocial alcoholism (Lappalainen et al. 1998),

suggesting specificity ofthis genetic etTect. Nielsen et al. (1998) observed linkage of

tryptophan hydroxylase (TPH) to OSM-ID-R alcoholi~ although not in atTected sib­

pairs; the evidence became stronger when alcoholics without ASP were analyzed. Other

studies used carly onset alcoholics, < 25 Yr. (Kono et al. 1997; Parsian, 1998), or

alcoholics with the ICD-I0 diagnosis ofASPD (Samochowiec et al. 1999; Sander et al.

1998). Candidate genes involved in neurotransmission (often involved in aggressive

behavior as weil) are putatively implicated in these studies, mostly by association:

monoamine-oxidase A, MAO-A (Parsian 1998; Samochowiec et al. 1999), serotonin 5­

RTf transporter (Hallikainen et al. 1999), serotonin SLC6A4 transporter (Sander et al.

1998), dopamine receptor DRD2 (Kono et al. 1997). The late onset, less heritable subtype

ofa1coholism is not 50 intensely studied, i.e. Tiihonen et al. (1999) reported association

ofthe COMT gene with this subtype ofa1coholism.

Alcoholism and Phenotype in Genome Scans

The genome scan in the COGA subset ofdensely affected families (Reich et al.

1998) defined alcohol dependence requiring bath the DSM-III-R and the Feighner et al.

(1972) criteria. A genome wide study in an American Indian population (Long et al.

1998), environmentally and genetically more homogenous, and with a very high

incidence ofalcoholism (perhaps up to 80% in men and 50% in women) defined alcohol

dependence according to OSM-m-R criteria. A multivariate, statistically derived

phenotype was used in one analysis ofa recent genome scan within the Collaborative

97

Study ofthe Genetics ofAlcoholism, COGA (Foroud et al. 1998). The latent class

analysis, using Il symptoms ofalcoholism in families ofhigh-risk alcoholic probands,

identified 4 p(ogressively more severe classes, where class 4 was exclusively

charaeterized with withdrawal symptoms. The two MOst severe classes were combined ta

provide sufficient sample size for sib-pair linkage analysis, in which the strongest

evidence for a potential suscePtlbility locus was found on chromosome 16 (Foroud et al.

1998). These subjects were a subset ofthose ftom the previously noted genome-wide

study ofalcohol dependence (Reich et al. 1998). In the COGA sample, Begleiter et al.

(1998) condueted genome scan ofthe P3 event-related brain potential amplitude, a lower

order phenotype associated with alcoholism as ootOO in the beginning ofthis section.

3.3. MAJOR ASPECTS OF PHENOTYPIC HETEROGENEITY IN ALCOHOLISM

Subtypes ofAlcoholism

The variable presentation ofalcoholism bas been recognized for a long time,

resulting in attempts to classify alcoholics into more homogenous subgroups. Historical

review of39 typologies from the early scieotific literature in the period 1850-1941 cao he

found in Bahor and Lauennan (1983). Bahor and Dolinsky (1988) published a

comprehensive review ofthe typology literature since 1941. The eaclier typologies were

more intuitive, rather than resulting from systematic study. Sioce the 1950's, empirically

derived typologies based on statistical comparisons ofa priori tbeoretically derivOO

subgroups, or the a posteriori statistical derivation ofhomogenous subgroups in

multivariate analysis, have become common in the literature (Bahor & Dolinsky, 1988;

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Hesselbroc~ 1983). Numerous variables ofdifferent types were used 10 classify

alcoholics, i.e. age, gender, patterns ofalcohol consumptio~ psychological measures

such as personality or cognitive ability, family history, psychiatrie comorbidity, biological

findings, educatio~ income, ete.

An overlap between classifications derived from different variables and

methodological approaches is noted (Bahor & Dolinsky, 1988; Hesselbroek, 1983). This

situation can he expected when alcoholism is viewed as a complex etiologica1 system

integrated by overlapping genetic and environmental etTects. A reœnt study reported

numerous cross.correlations hetween subgroups based on Il representative typologies of

alcobolism (penick et al. 1999). Ali typologies showed a degree ofclinical validity and

no one typology was clearly superior. Hence different typologies may he useful to a

degree, while remaining at least partly distinct, consistent with the view that ditTerent

classifications may need to he developed to tap information pertinent to different

purposes (Bahor & Dolinsky, 1988; Hesselbrock, 1983), i.e. various aspects oftreatment,

prevention, and researcb.

A widely accepted consensus from the extensive typologicalllterature is that two

broad categories ofalcoholics can be identified, with one showing earlier onset of

alcoholism, more psychiatrie comorbidity, increased frequency ofalcoholism and

comorbid psychopathology in biological relatives, greater severity, and poorer prognosis

(Bahor & Dolinsky, 1988; Penick et al. 1999). An overview ofMOst influential recent

typology research is presented below.

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3. 3. 1. Early Onset and Late Onset Alcoholism

The age ofonset maintains a central position in delineating two broad subgroups

ofalcoholics throughout the past century ta present. An early typology, proposed by

Knight in 1937, descnbes the Essential and Reactive alcoholism (penick et al. 1990). The

Essential alcoholism had an earlier age ofonset ofabusive drinkïng, more severe

alcohoiism, no relation to environmental stressorslt and was linked 10 a positive family

history ofalcoholism, while the opposite pattern characterized Reactive alcoholism. This

broad distinction remains largely unchanged in various more recent fonnulations.

OperationaI Classification by the Age ofOnset

A particularly influential classification ofalcoholism was initially proposed in a

study ofadopted men by Cloninger et al. (1981), in a series ofmultivariate statistical

analyses. The more heritable Type 2 alcoholism showe~ in the biological father,

extensive treatment and characteristic combination ofearly-onset severe alcohol abuse

and severe criminality, no postnatal environmental effect on the frequency ofalcoholism

in sons, more severe alcoholism, and no alcohol abuse in biological mothers (Cloninger

et al. 1981). This etiological typology ofalcoholism from the adoption study was

subsequently transfonned into a proposai for explicit diagnostic Type 1 and Type 2

criteri~ to be applied to alcoholic individuals (Gilligan et al. 1988). Proposed criteria

included two elements: 1) age ofonset > 2S YT. for Type 1 alcoholism, or < 25 YT. for

TyPe 2 alcoholism; 2) two or more symptoms characteristic ofTyPe 1(benders, guil~

loss ofcontrol, cirrhosis) or Type 2 (inability to abstai~ fights while drinking, drunken

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driving, treatment for alcohol use) alcoholism. In contrast ta this dichotomous proposai,

the same group also stated that Type 1and Type 2 should not he considered discrete

entities because many a1cohol abusers have some features ofeach type (Cloninger, 1987;

Sigvardsson et al. 1996). The latter view was supported in subsequent failures to classify

MOst alcoholics into either Type 1or Type 2 as per proposed criteria, due ta the presence

ofboth Type 1 and Type 2 features (Glenn & Nixon, 1996; Penick et al. 1990; Sannibale

& Hall, 1998). However, the 25 yr. age ofonset cutoft: without symptomatic criteria,

differentiated alcoholics along a variety ofclinical and biochemical measures (Glenn &

Nixon, 1991; Glenn & Nixon, 1996; Pennick et al. 1990; Von Knorring et al. 1985),

leading to the conclusion that Cloninger's classification primarily reflects the age ofonset

(Pennick et al. 1990).

The proportion ofsubjeets classified as early onset « 2S Yf.) can vary depending

on the theoretical construct whose onset is defined, i.e. 44% for "regular drunkenness

began" to 20% for "realized own problem" (parella & Filstead, 1988). These are

primarily self-reported constructs whose definition varies between studies. For example,

Glenn and Nixon (1996, 1991) used the age ofonset for the majority of7 symptoms,

Pennick et al. (1990) used reported age at which problems with alcoholism first began,

Von Knorring et al. (1985) used reported age ofonset ofsubjective drinking problems. In

addition, sorne investigators choose a different age cutot[ Buydens-Branchey et al.

(1989a, 1989b) defined early onset as excessive drinking before 20 yr., and Pennick et al.

(1999) defined early anset as the first experience ofany problems associated with

drinking before 24 yr. ofage. The onset ofalcoholism is a developmental sequence rather

than a discrete even~ and the earlier cutoff for excessive drinking might he comparable to

101

the later cutofffor subjective drinking problems, as the fonner stage precedes the latter

stage (Buydens-Branchey et al. 1989a; Parella & Fillstead, 1988). In summary, the

developmental nature ofalcoholism allows for varied conceptual and numerical criteria

for defining early and late onset alcoholism (parella &, Fillstead, 1988), within which two

broadly different subgroups ofalcoholics can he identified.

Age ofOnset and Major Recent Classifications ofAlcoholics

The MOst influential recent classifications (pennick et al. 1999) include

Cloninger's Type 1and Type 2 alcoholism (Cloninger et aL 1981), primary versus

secondary classification based on comorbid disorders (Schuckit, 1985), and a multivariate

empirical classification based on indices ofvulnerability and severity (Babor et al. 1992).

Cloninger incorporated bis original proposai ofType 1, late onset and Type 2,

early onset alcoholism (Cloninger et al. 1981), noted previously, into a more

comprehensive neurobiological theory ofalcoholism, including dimensions of

temperament (Cloninger, 1987; Cloninger, 1995). According to Cloninger (1987),

Novelty Seeking (NS) distinguishes individuals who are impulsive, exploratory,

excitable, distractible (high NS) and those who are rigid, refleetive, and attentive to

details (Iow NS). Harm Avoidance (HA) differentiates apprehensive, inhibited, shy,

cautious, pessimistic (high HA) from the confident, relaxed, optimistic, uninhibited and

energetic (low HA). Reward Dependence (RD) differentiates empathie, emotionally

dependent, sentimental, sensitive to social eues, and persistent (high RD) from the

socially detached, emotionally cool, praetical, tough-minded and independently self­

willed (Iow RD). The Type 2 (early onset) alcoholies were proposed to he high in Novelty

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Seeking, low in Harm Avoidance and Reward Dependence, and associated with antisocial

personality, while Type 1 alcoholies were proposed to show the opposite temperamenta1

pattern and an association with depression and anxiety (Cloninger, 1987; Cloninger,

1995). The Type 1 and Type 2 were not viewed as discrete entities, but as polar

prototypes on the continuum, acknowledging that combinations ofabove discussed

independently inherited temperament dimensions provide extensive heterogeneity in

behavioral predisposition to alcoholism (Cloninger, 1987; Cloninger, 1987b; Cloninger et

al. 1991; Sigvardsson et al. 1996; Svrakïe et al. 1993). In agreement with this complexity,

only high Novelty Seeking was consistently shown to prediet early onset abusive drinking

and discriminate antisocial alcoholies and persons with ASPD ftom their non-antisocial

counterparts (reviewed in Howard et al. 1997).

Schuckit (1985) detennined primary psychiatrie diagnoses in 541 men entering

alcohol treatmentpro~ ofwhom ail but two met criteria ofalcohol abuse and/or

dependence as per DSM-m and ROC. A primary diagnosis ofASPD (7.3%) was made

when individual met both the DSM-m and ROC criteria for definite or probable ASPD

before the age offirst major life problems due to alcohol or drugs. A primary diagnosis of

drug abuse (Il. 1%) was made when the first major life problem due to drugs preceded

the tirst major life problem due to alcohol. Primary affective disorder (1.7%) was

diagnosed when criteria for major affective disorder were met prior to the first major life

problem due to alcohol, or following an abstinence ofthree or more months. The

remaining 79.9% ofsubjeets were primary alcoholies. The age ofonset ofalcoholism was

defined as the age at which individual first met the alcoholism criteria stated above. The

age ofonset was lowest in primary drug abusers and primary ASPD subgroups (24.5 ± 5

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and 25.0 ±6.8 yr. respectively), as opposed ta 36.6 ± 12.4 and 35.0 ± 10 yr. in primary

alcoholics and primary affective disorder subgroup, respectively. The early onset

subgroups had more depressioD and a higber frequency ofalcoholism, depression and

drug abuse among first-degree relatives.

Bahor and coworkers (1992) used cluster analysis to derive subtypes among 228

males and 85 females who met OSM-ID criteria for alcohol dependence (96%) or abuse

(4%). A total of 17 variables were used in the analysis. Premorbid risk factors were:

familial alcoholisrn, childhood disorder, bipolar character dimensions, and the onset of

problem drinking. Indices ofalcobol and other substance use were: quantity ofalcohol,

reliefdrinking, alcohol dependence severity, benzodiazepine use, and polydrug use.

Variables descnbing chronicity and consequences ofaIcoholism were: physical

conditions, physical consequences, social consequences, lifetime severity, and years of

heavy drinking. Psychiatrie symptoms were depression symptom count, antisocial

personality symptom count (DSM-llI), and severity ofanxiety. The 2-eluster solution,

Type A and Type B, was identified for bath genders (N = 107 and 121 respectively in

males, versus 53 and 32 in females). These types were differentiated on ail entered

variables in males and on 13117 variables in females (no difference for benzodiazepine

use, reliefdrinking, depressive symptoms and anxiety), as expected because c1uster

solutions were derived from these variables. Except for the age ofonset and years of

heavy drinking, the Type B had higher values ofditTerentiating variables (more

pathology) in bath males and females. The age ofonset ofproblem drinking for Type A

was 30.34 ± 9.80 yr. in males and 34.20 ± 10.50 in females, and for Type Bit was 21.70

± 5.36 in males and 21.46 ±4.59 in females. These authors have also validated obtained

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elusters by examining variables that were not entered in the eluster analysis, namely

personality measures, drinking history, a1cohol..related consequences, and clinical ratings,

showing substantial differentiation betweeo the Type A and Type B (Babor et. al 1992).

In summary, the similarity between methodologically diverse classifications of

alcoholies a100g a number ofparameters ioeluding early onset ofalcoholis~antisocial

behavior and polysubstance abuse is striking, notwithstanding sorne differeoces in other

psyehopathology. For example, Penniek et al. (1984) found an association ofASPD and

depression in a study ofmale aleoholics, Babor et al. (1992) found an association

between depression and ASPD in male but not fernale alcoholics, and Hesselbrock et al.

(1984) did not find this association in either gender. These discrepancies cao he expected

because alcoholics with ASPD differ with respect to the presence ofother psychiatrie

disorders (Liskow et al. 1991). Overall, in both genders there is a subgroup associated

with the earlier onset ofalcoholism, childhood and adult antisocial behaviors,

polysubstance abuse, higher frequency ofalcoholism and comorbid psychopathology in

biological relatives, greater severity ofalcoholism and poorer prognosis, al least with

conventional treatments (Babor et al. 1992; Cloninger et al. 1981; Cloninger, 1995; Glenn

& Nixon, 1991; Hesselbrock et al. 1984; Kendler et al. 1998; Longabaugh et aL 1994;

McGue et al. 1997; Penick et al. 1984; Schuckit, 1985). Results ofthe exploratory factor

analysis in the comparative study of Il alcoholism typologies (Pennick et al. 1999) are in

agreement with these data. The following 3 dimensions, explaining 35°At ofvariance,

were suggested to account for significant overlap between alcoholism typologies: a) age

and age correlates including the age ofonset; b) "pure" versus psychiatrically

lOS

heterogenous alcoholism that encompasses antisocial personality disorder; c) current

severity ofpsychiatrie distress, impairment and dysfunction.

3. 3. 2. Alcoholism and Antisocial Personality Disorder

Association ofA1coholism and ASPD

In the Epidemiological Catchment Area (ECA) study in the United States,

antisocial personality disorder was the disorder most strongly associated with alcoholistn,

with the estimated odds ratio of21 (Helzer & Przybeck, 1988). The 15% ofmen and 10%

ofwornen with a lifetime diagnosis ofDSM-ID-R alcohol abuse or dependence a1so met

the diagnostic criteria for ASPD, compared to general population ASPD rates of4% in

men and 1% in wornen. Conversely, lifetime prevalence ofalcohol abuse of74% was

found among those with ASPD, compared to 14% in the general population (Regier et al.

1990). Similar results were obtained in the National Comorbidity Study, where only drug

disorders were more strongly associated with alcohol disorders (Kessler et al. 1994;

Kessler et al. 1997), as weil as in the epidemiological study conducted in Canada (Ross,

1995). Generally, the rates ofASPD are higher among alcoholics receiving treatment than

among those identified in the general population, i.e. ranging from 25-56% for men and

19-30% for women (Penick et al. 1988; Ross, 1989; Ross et al. 1989; Thomasson &

Vaglum, 1995). This is consistent with previously noted greater severity ofalcoholism

with comorbid ASPD, and the ASPD might a1so he a factor that facilitates identification,

and institutionalization in particular, for treatment ofalcoholism.

106

Longitudinal Studies

In accordance with the strong association between alcoholism and ASPD, which

by diagnostic definition includes childhood antisocial behavior, longitudinal studies have

found that childhood antisocial behavior prediets abusive drinking (reviewed in Zucker &.

Lisansky.<Jomberg, 1986). More specific longitudinal studies found that childhood

antisocial behavior predicts an earlier onset ofa1coholism (Cloninger et al. 1988~ Jessor

&, Jessor, 1975), consistent with the previously noted association between ASPD and

early onset alcoholism. Jessor and Jessor (1975) followedjunior high school students

(grades 7, 8 and 9) for 4 years, and found that generally deviant behavior (lying. stealing.

cheating, aggression) predieted an earlier onset ofdrinking in both boys and girls

Cloninger et al. (1988) followed 233 boys and 198 girls from a detailed behavloral

assessment at Il yr. to the age of27 yr., when abusive drinkers were identified from

Temperance Boards, drunken driving or other drinking arrests, treatment for alcohohsm

or its complications, or a psychiatric diagnosis ofalcoholism. Novelty seeking. raled

using teacher's interview report ofchildhood antisocial behaviors (e.g. overaCllvc.

disorderly, excitable, violent temper tantrums, obtrusive/disruptive... ) predicted abUSive

drinking in boys. The relative risk ofabusive drinking was 2.4 for boys high ln no\(el~'

seeking as compared to the total population. The faet that only 21198 girls were .denttfied

as abusive drinkers may relate to secular trends, which increase prevalence ofalcoholism

in more recent generations (Reich et al. 1988; Stoltenberg et al. 1999). Currently in

progress is a Michigan State University Longitudinal Study (Zucker et al. 1994)~ however

these subjects were only 9-11 years old at the last, wave 3 assessment (Leonard et al.

2000).

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Family, Twin and Adoption Studies

Family studies examining the rates ofantisocial behavior in relatives ofalcoholic

adults (Amarlc~ 1951)~ the rates ofalcohol dependence in parents ofchildren with conduct

disorder (Stewart et al. 1980)~ or the rates ofconduet disorder in the otfspring of

aleoholic parents (Lynskey et al. 1994)~ found evidence for cross-transmission of

alcoholism and antisocial behavior. Twin studies provide evidence for common genetic

factors in alcoholism and conduct disorder or ASPD (Grove et al. 1990; McGue et al.

1992; Pickens et al. 1995; Slutske et al. 1998). Slutske et al. (1998) examined OSM-m...R

Iifetime diagnoses ofconduct disorder and alcohol dependence assembled from the

telephone interview in a sample of2682 twin pairs~ including males and females. Genetic

influences common to conduet disorder and a1cohol dependence accouoted for 17% and

35% ofthe genetic variation in Iiability to alcohol dependence in men and women,

respectively~ and for 11% and 23% of the totalliability variation in men and women~

respectively. On the other han~ adoption studies generally suggest that alcoholism and

antisocial behavior are genetically independent~ because there is no cross-trait association

between biological parents and their adopted away offspring (Cadoret et al. 1985;

Cadoret et al. 1987; Cadoret et al. 1995). This discrepancy could in part result from the

diminished power ofadoption studies to detect genetic covariation between traits in

comparison to twin studies (Slutske~ 1998; Waldman & Slutske~ 2000).

Symptomatic Behavioral Complexity ofthe Earlr Onset Antisocial Alcoholism

The data thus far suggest that alcoholism and ASPD share some proportion of

underlying genetic variance. Translation ofthis findiDg towards a phenotypic definition

108

useful for genetie mapping studies in alcoholism, however, is complicated by the

complex developmental nature ofthese disorders al the diagnostic level.

Variation along broad, genetically influenced Personality dimensions of

neuroticismlemotionality, extraversionlsociability and, especially,

impulsivity/disinhibition is related in various degrees to bath alcoholism and ASPD

(reviewed in Sher & Troll, 1994). Both ASPD and alcoholism are thought 10 he

composed ofat lcast two broad subtypes, the more psychopathie (impulsiveldisinhtbited)

and the more neurotie subtyPes (Sher & Trull, 1994), although individuals ean show

extreme levels ofboth impulsivity and neurotieism (MeGue et al. 1997). Loeher (1990)

distinguished the "Aggressivelversatile" Path leading to wide-ranging antisocial behavior,

with the onset in preschool years, and the '~onaggressive antisocial" l'8th leading ta

more specialized offending, with the onset in adolescence. At present, the DSM-IV

indirectly aeknowledges the heterogeneity ofASPD by subtyping conduct disorder (CD),

which is required for the diagnosis ofASPD, into the early onset «10 yr.) often

aggressive subtype, and the adolescent onset subtype (APA, 1994).

Failure to account for likely heterogeneity within the diagnostic category ofASPD

might hinder identification ofgeoetic risk factors whose common effect on ASPD and

abusive drinking is mediated by more specifie phenotypie components. Thus far, Most

studies examining the relationship between alcoholism and ASPD were oot designed to

take iota account potential heterogeneity with respect 10 the pattern ofspecifie antisocial

behaviors, employing instead piecemeal records information (e.g. Cloninger et al. 1981),

diagnosis ofASPD (e.g. Schuckit, 1985), or ASPD symptom count (e.g. Bahor et al.

1992; Zucker et al. 1994). A recent latent class analysis of38 ASPD and CD symptoms

109

was perfonned in a sample ofbigh-risk (strong family history ofa1coholism) alcoholic

probands (19.4%), their relatives (71.1%), and controls (9.5%) ftom the Collaborative

Study on the Genetics ofAlcoholism (COGA) group (Bucholz et al. 2000). Latent class

analysis is a categorical analog offactor analysis that identifies unobserved classes which

MaY he interpreted as discrete or as parts ofthe continuum, dePending on whether class

prevalences ofspecifie symptoms change abruptly or not (McCutcheon, 1987). The study

asked whether there are subtypes ofASPD with distinct symptom patterns.. and whether

certain ASPD symptoms are particularly strongly associated with alcohol dependence.

The results from both males and females supported the interpretation ofthe disorder

distributed on a continuum ofseverity (Bucholz et al. 2000). Among females. a 4-class

solution was obtained with OSM-ill-R lifetime conduet disorder and ASPD round almost

exclusively in the·most severe elass. Among males, a S-class solution was obtalned wilh

the highest prevalence ofASPD in the most severe class. The relationship of latent

classes to alcoholism, i.e. the age ofonset and prevalence ofOSM-m...R lifetime alcohol

dePendence, was largely consistent with generally observed carlier onset and Increased

prevalence ofabusive drinking in antisocial individuals. The non-representauvc

character ofthe analyzed population, intended to maximize the potential for genetlc

studies in alcoholism (requiring at least two affected first-degree relatives. among other

criteria), limits the generalizability ofresults (Bucholz et al. 2000). Moreover. a critlcal

assumption of latent class analysis is that within each class symptom frequencies are

statistically indePendent; therefore ail individuals are assumed to have an equal

probability ofshowing a certain symptom pattern calculated by multiplyjng symptom

frequencies (McCutcheon, 1987). In view of the familial charaeter and covariation of

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ASPD and alcohol~ this assUlDption is ignored as Most ofthe analyzed individuals

were family memhers ofaIcoholic probands; they might therefore he more likely to show

a symptom pattern similar ta tbat found in the proband Also, family members are

expected to he similar but not identical ta the proband, and might therefore bias the

results towards a continuous solution by diminishing potential distinctions between

probands.

Kendler et al. (1998) applied latent class analysis to data from Temperance Board

Registrations in a sample of2505 male twins from the population-based Swedish Twin

Registries. Among other variables, the data included drunkenness, drunken driving, and

crime, and were thus less informative for specific patterns ofantisocial behaviors than the

data from above discussed COGA study (Bucholz et al. 2000). In contrast ta the COGA

study, the results showed qualitative ditTerences, particularly in causes of registration

noted above. The latent class with early onset o( and multiple, TBR registrations

(prevalence 30%), showed a distinctly strong endorsement for drunkenness, drunken

driving, and crime, as compared to 3 classes that strongly endorsed either drunkenness, or

drunken drivin& or crime.

The COGA study was not designed to examine the latent structure ofantisocial

behaviors among alcohol-dependent individuals. By definitioo, individuals affected with

a complex disorder such as alcohol dependence have a constellation ofrisk factors and

potential modifiers sufficient for the expression ofthe phenotype. This constellation may

influence antisocial behavior via the impact ofalcohol dependence, via the presence of

common genetic factors and lor through other means, 50 that the latent structure of

antisocial behaviors in alcohol-dependent individuals might not he the same as that found

111

in other populations. This latent structure is investigated in the present manuscript in

submission, entitled "Exploring Phenotypes in A1coholism: Unrestrieted Latent Class

Analysis ofAntisocial Bebaviors in Alcohol Dependent Males and Females with Diverse

Social Adjustment'7.

3. 4. SUMMARY

A1coholism is a complex and heterogenous behavioral disorder, sharing genetie

risk factors with antisocial personality disorder, among other phenotypes. Phenotypes,

and by extension molecular genetie mapping studies, in alcoholism did not take ioto

account potential differentiation with respect to the pattern ofantisocial bebavioral

symptoms amoog alcoholics, although some studies focused 00 violent alcoholics. The

literature documents substantial clinical and biochemical heterogeneity between the

early- and late-onset subgroups ofalcoholics. The first study in the present work explores

whether subgroups ofalcohol.dependent individuals with distinct patterns ofspecifie

antisocial behaviors can be empirically defined. The second study explores the impact of

stratification into the early- and the late-onset subgroups ofalcoholies on results ofthe

initial genome scan. These phenotype-oriented approaches might ultimately increase the

power for identification ofspecifie genetic effects.

112

3(8). EXPLORING PHENOTYPES IN ALCOROLISM: UNRESTRIcrED

LATENT CLASS ANALl'SIS OF ANTISOCIAL BEHAVIORS IN ALCOHOL

DEPENDENT MALES AND FEMALES WITR DIVERSE SOCIAL

ADJUSTMENT

The present chapter coosists ofthe following manuscript in submission, entitled

as above.

113

Exploring Phenotypes in Alcoholism: Unrestrieted Latent Class Analysis

ofAntisocial Bebavion in Aleobol Dependent Males and Females with

Divene Social Adjustment

ILUA KOVAC·, CHANTAL MERETI'E2, MIREILLE CAYER2

, LUCIE LEGAULT3,

MAURICE OONGIER3•4 and ROBERTA M. PALMOUR1.J.4,5

McGill University

Supported in part by grants from the Medical Research Council ofCanada, the National

Health Development Research Program and the Réseau Santé Mentale of the Fonds de

Recherché en Santé du Québec. This work is in partial fulfillment ofthe requirements for

the Ph.D. degree (I1ija Kovac).

Departments ofBiologyl, Human Genetics4, and Psychiatry5 , MeGiIl University,

Montreal, Quebec, Canada; Centre de Recherché Université Laval Robert-Giffard2,

Québec, Canada; Douglas Hospital Centre de Recherche3, Verdun, Québec, Canada

Correspondence to:

Dr Roberta Palmour

Department ofPsychiatry, McGill University, Allan Memorial Institute, Research and

Training Building Room 307,1033 Pine Avenue West, IDA lAI, Montreal, Quebec,

Canada. Tel. (514) 398-7303; Fax (514) 398-4370; E-mail: mc23@musica.mcgill.ca

114

•

ABSTRACf

Backgroud. Perhaps the best accepted distinction with respect to helerogenous

suhtypes ofalcoholism is the early onset and antisocial alcoholism versus late onset

alcoholism. The present study, in the Montreal sample ofthe WHO-/SBRA Study ofState

and Trait Markers ofAlcoholism, formally examines whether subgroups ofalcohol­

dependent individuals with distinctive patterns ofspecific antisocial behaviors can be

empirically dejined Metbods. An unrestricted latent class ana/ysis (LCA), inc/uding

gender and 15 antisocial behaviors expressed after 15yr ofage, was perjOrmed in 236

subjects (121 males and 115fema/es) with D8M-/Vdiagnosis ofa/cohol dependence;

subjects were ascertainedfrom clinica/ (690/6 ofmales, 30% offema/es) and general

population sources, andshowed a wide range ofsocial adjustment. Latent classes were

validated by comparing age ofonset fOr a/cohol dependence, frequency ofalcoho/icjirst­

degree relatives, and other psychopalhology, us;ng a multivariate index ofchildhood

behavior obtained by independently conducting an LCA of12 conduct disorder

symptoms. Results. Evidence fOr 3 qualitative behavioral classes with potenlial

interpretative value was obtained: Social/y Adjusted Adu/ts (SM, N = 62, 23 males, 39

jema/es), Antisocial Non-Aggressive Adu/ts (ANAA, N = 138, 77 ma/es, 61 jémales), and

Antisocial Aggressive Adu/ts (MA, N = 36, 21 male, 15tema/es). The LCA ofchildhood

behaviors identified 3 classes comparable 10 adu/t classes. In bath ma/es and[ema/es, the

AM c/ass had the ear/iest age ofonsetfor a/cohol dependence (p=O.OOI), an increased

proportion ofalcoho/icfirst-degree relatives and an increasedprevalence ofo/her

psychopathology, whi/e the SM c/ass showed the opposite pattern. ln féma/es. the ANAA

115

c/ass was intermediate. ln ma/esfrom the ANM c/ass. socially adjusted chi/dhood

behavior differentiated the /ale onset subgroupfrom the intermediate onset subgroup.

CODelusions. The present multivariate exploration suggests a comp/ex structure of

qualitative hehaviora/phenotypes rather than continuous variation ofantisocial

behaviors among alcoho/-dependent individua/s. A bener understanding ofthe types of

heterogeneity in a/coho/ism mayfacilitate the identification ofrisklactors.

Keywords:

alcohol abuse, alcohol dependence, antisocial bebaviors, latent class analysis

RUDDing bead:

Latent Structure ofAntisocial Behaviors in Alcoholism

116

INTRODUCTION

There is presendy a broad consensus that elinically diagnosed a1coholism

represents a heterogenous condition (Bahor, 1994). Heterogeneity among alcoholic

individuals is likely to hinder not ooly treatment efforts (Longabaugh et al. 1994), but

also the detection ofspecifie geoes which might increase vulnerability 10 the disorder

(Lander and Sehor~ 1994). Alcoholism overail May he viewed as a complex etiological

system integrated by overiapping actions and interactions ofvarious genetie and

environmental effects. In this integrated eontext it is not surprising that altemate

typologies ofalcoholism variously based on parameters such as drinking patterns, family

history, PSychiatrie co-morbidity, psychological and physiological measurements, show

significant cross.correlations when relatively simple or multivariate empirical approaches

are employed (penick et al. 1999).

One ofthe best accepted facets ofdiiTerentiation (peniek et al. 1999) is

alcoholism associated with antisocial behaviors, i.e. criminal records, diagnoses ofASPD

(Antisocial Personality Disorder), and/or ASPD symptom count (Cloninger et al. 1981;

Peniek et al. 1984; Hesselbrock et al. 1984; Cloninger 1995; Schuckit, 1985; Schuckit et

al. 1986; Hesselbrock et al. 1985; Bahor et al. 1992; Longabaugh et al. 1994; McGue et

al. 1997; Kendler et al. 1998). This broad type ofalcoholism is charaeterized by an earlier

age ofonset, an increased ftequeney ofalcoholism in first-degree relatives, increased

rates ofdrug use and childhood behavioral problems, more severe alcoholism and

differenl treatment outcome. Although il was suggested that this type ofalcoholism, also

tenned Type 2 alcoholism, might he limited to males (Cloninger et al. 1981; Bohman et

117

al. 1981), early onset and antisocial alcoholism is found in females as weil (Hesselbrock

et al. 1984; Glenn and Nixon, 1991; Babor et al. 1992).

A recent study in a large sample oftwins suggested that genetic factors common

ta alcohol dependence and conduct disorder (a precursor ofASPD) account for 11% and

23% ofthe total variation in liability ta alcohol dependence in males and females,

respectively (Slutske et al. 1998). Struetured exploration ofspecifie signs and symptoms

may suggest distinct phenotypes whieh will ultimately permit detection ofmore specifie

vulnerability genes. The diversity ofspecifie antisocial behaviors is reflected in the

operational DSM·IV coding ofdifferent higher order criteria for ASPD, ineluding

unIawful behavior, deceitfulness, impulsivity or failure to plan ahead, irritability and

aggressiveness, recldess disregard for the safety ofselfor others, consistent

irresponsibility, and laek of remorse (APA., 1994). Neither the threshold diagnosis nor the

symptom count score capture the potential for ditTerentiation of individuals based on

variable patterns ofantisocial behaviors. Rather, a fonnal multivariate statistical model

that explicitly postulates such differentiation can he used to investigate novel phenotypie

definitions ofalcoholism with increased dimensionality, potentially allowing for more

meaningful interpretation.

In the present study, we use the information from the Montreal arm ofthe WHO.

ISBRA Study ofState and Trait Markers ofAlcoholism (Tabakoffet al. 1996) to conduct

exploratory analyses ofsubtypes ofalcohol dependent individuals derived from ASPD

symptoms, using the multivariate categorical technique of latent class analysis (LCA).

The LCA is intuitively similar to a quantitative factor analysis and postulates mutually

exclusive classes of individuals which best account for the observed frequencies of

118

•

bebavioral symptoms (McCutcheon, 1987). Under this assumption, we examined the

latent structure ofdiverse antisocial bebaviors among alcohol dependent males and

females showing a wide range ofsocial adjustment

SUBJECrS AND METHODS

Subjects

The WHO-ISBRA Study ofState and Trait Markers ofA1coholism is a

multinational investigation carried out in Australia, Brazil, Canada, Finland, Ja~

Sweden and the United States. Montreal is one of5 clinical centres in this project

(Tabakoffet al. 1996). Ali participating centres recruited approximately equal numbers of

male and female non-drinkers, light drinkers, heavy drinkers (reflecting alcohol

consumption in the last 3 months) and alcoholics in treatment in three equally

represented age groups: 18-29, 30-44 and 45-60. A total of297 females and 310 males

were reeruited in Montreal. Ali of these subjects were in good physical and mental health,

apart from possible alcohol problems, as determined by interview and physical

examination. Subjects sutfering trom major medical or psychiatrie disorders, and those

with a history of intravenous drug abuse were excluded. Written informed consent was

obtained from each subject.

The present exploratory analysis includes 121 male and 115 female subjects

recruited in the Montreal centre who met DSM-IV criteria for alcohol dependence in the

past year, regardless oftheir age group or drinking group. Among the 121 male subjects,

83 (69%) were recruited from a1cohol and/or drug treatment facilities (28 from the

119

detoxification clinic, 30 ftom the rehabilitation program and 25 ftom the combined

detoxificationlrehahiütation program) and 38 (31%) were identified ftom the general

population tbrough newspaper advertising. Among the 115 female subjects, 35 (30%)

were recruited ftom treatment settings (4 ftom the detoxification clinic, 11 ftom the

rebabilitation program, 20 ftom the combined program) and 80 (70%) ftom the general

population through newspaper advertising. Other diagnostic aspects ofaIcoholism and

demographic information are presented in the results.

Data collection

An initial telephone screening was carried out with subjects who had answered a

newspaper advertisement. The subjects considered suitable were given an appointment

for the interview, at which time a physical examination was perfonned and blood and

urine samples were callected. The subjects, except the alcoholics in treatment, were

provided with a 540 (eN) stipend at the end ofthe session.

Interviewers were trained in the use ofan instrument (The WHo-lSBRA

Interview Schedule), developed especially for this study by Bridget Grant and Boris

Tabakoff. Dr. Grant trained the initial group ofMontreal interviewers. A summary

description ofthe WHO/ISBRA Interview Schedule can he found in Tabakoffet al. 1996.

The kappa values for making a OSM-IV diagnosis ofalcohol abuse and dependence with

this instrument ranged from 0.60 to 0.80 (TabakotI: 1996). Overall, this struetured

interview instrument cantains 8 sections: Intake Screening, Recruitment Setting,

Background Information, Medical Conditions, Alcohol Consumption, Alcohol

Experiences, Substances and Personal History, and Family History section, with the latter

120

two sections including information on other psychopathology. The instrument required

between 30 minutes and 2 hours for completio~ depending on the subject's profile. A

diagnosis ofDSM-IV alcohol dependence in the past year was recorded by the selection

ofappropriate questions from the A1cohol Experiences section ofthe WHO/ISBRA

Interview Schedule.

Variables

Two sets ofbehavioral variables were used in latent class analyses (LCA).

Symptoms occurring after 15yr ofage (abbreviated here as ASPD symptoms) Of, ln a

separate LCA, before 15yr ofage (CD or conduct disorder symptoms) are described in

Table 1, and prevalence ofthese behaviors by gender is shown in Table 2. Thcsc

bebaviors were coded in the "Substances and Personal History" section ofthe

WHO/ISBRA Interview Schedule. Among ASPD symptoms, 3 variables pertalnlng to

childcare (not shown in Table 1) were not included in LCA because ofextremely low

frequencies « .01). In order to assess whether the ASPD symptom-based latent classes of

alcohol-dePendent subjects differ in other relevant aspects, we have contrasted extemal

variables (not included in the LCA ofASPD symptoms) between these classes. The

extemal variables we examined were: age, age ofonset for alcohol dependence.

proportion ofalcoholic first-degree relatives, childhood behavioral problems.. drug use.

lifetime depression, and anxiety. The age ofonset ofalcohol dependence was considered

to he the age at which symptoms first began to appear. First-degree relatives were

considered to be alcoholic ifthe infonnant could report that 80y of 18 alcohol-related

experiences had happened MOst days for at least a month, or intermittently for a few

121

•

•

Symptom

Adult behaviors(> IS yr.):

not working

absent from workquit jobtraveledno homeliedbillsstoledamagebun persanweaponscamunfaithfuIarrestcould he arrested

Childhoodbehaviors« 15 yr.):

hooky

suspendednmawayliedstoledamagefightsweaponhurt personhurt animaltirearrest

Table 1. Adult and Childhood Antisocial Behaviors

Description

were unemployed or out of school for 6 montbs or longer wben you shouJd bave beenworking or in schaolwere often absent from work or school for no goOO reasonquit 3 or more jobs without makïng plans to find other jobstraveled around from place ta place without making plans ahead oftimehad no reguJar place to live for a month or longertold a lot oflies or used a false name or aliasfailed to pay your bills or other financial obligations on a regular basismore than once stole things from your family or others (mcluding stores)damaged anotber persan's property on purposeinjured or burt ancther persan on purposeother than in combaty used a weapoo lite a ciuby knife or sun. in a fightscammed or conned someone for money or just for funnever remained faithfuI ta the same penon for longer than a yearwere arrested by the police for anything other tban a traffic violationdid anything you could have been arrested for even though you weren't caught (notincluding drunk driving)

did not go to schaol (played hooky) without a medical or other good reason for anentire day at least twice during one yearwere suspended or expeUed from schaolran away from home ovemight or longertold a lot ofliesmore tban once stole things from your family or others (including stores)damaged another persan's property 00 purposestarted physical fights with non-relatives 3 or more timesused a weapon (like a club, knife or gun) in a fightoutside offighting, injured or hun another persan on purposeinjurecl or hurt an animal on purposestarted a tire on purpose ta injure another penon's propeny or just to see it bumdid anything you were arrested for (mcluding going ta juvenile detention) or could havebeen arrested for even though you weren't caught

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Table 2. Prevalence ofAntisocial Bebaviors by Gender

Prevaleoce (%)

Males Females

N= 121 N=1l5

Adultbehaviors(> 15 yr.):

ootworking 38.0 33.0absent from work 48.8 43.5quit job 28.9 20.0ttaveled 35.5 33.000 home 22.3 23.5lied 42.1 41.7bills 57.9 52.2stole 24.8 34.8damage 13.2 7.0hunperson 21.5 14.8weapoo 11.6 6.1seant 25.6 15.7unfaithful 30.6 26.1arrest 37.2 26.1could be arrested 51.2 39.1

Childhoodbehaviors« 15 yr.):

hooky 50.4 49.6suspended 33.1 29.6runaway 20.7 34.8lied 50.4 53.0stoIe 37.2 49.6damage 27.3 17.4fights 28.1 20.0weapoo 10.7 6.1OOn persan 13.2 14.8hunanimal 9.9 2.6fire 6.6 6.1arrest 25.6 21.7

123

months or longer. A multivariate index ofchildhood behavioral problems was obtained

by the LCA ofCD symptoms, conducted independently ftom the LCA ofASPD

symptoms. Drug use was defined as either psychoactive drug use (other than tobacco) in

the last 30 clays or having lifetime drug related problems. These variables were selected

because they can differentiate alcoholism associated with antisocial behaviors~ as

descnbed in the introduction. Wc bave also examined the distnbution of lifetime

depression and anxiety among latent classes, as potentially relevant ta suh-classification

(Del Boca, 1994}, as weil as the distribution of individuals with 3 or more CD ~mptoms.

Lifetime depression was coded positive ifsubject was 50 depresse~almost ail day cvery

day for 2 weeks or longer, that helshe couldn't carry on usual daily activities. Lifetlme

anxiety was coded positive ifsubject 50ugbt help for anxiety.

Latent C/ass Analyses (LCA)

The LCA is a multivariate statistical method for the analysis ofcategoncal data in

multi-way contingency tables. The latent class model postulates that observed symptom

frequencies can he explained by the categorical latent variable with mutually exclusive

classes~ within which observed variables are statistically independent (assurnpuon of

local independence). Parameter estimates of the latent class Madel include: class

membership probabilities at the level of the observed population which can he IOterpreted

as class frequencies; class membership probabilities at the level of individuals

conditiona] on the membership in a given class; and symptom endorsement probabilities

(SEPs) that reflect the probability of individual endorsing a SYmptom conditional on class

membership. The overall profile ofSEPs is characteristic for each class. The LCA

124

classification assigns the individual to the class for which hislher conditional probability

ofmembership is greatest. The model estimates oflatent class prevalences and SEPs

were very similar to the values observed on the basis ofLCA classification, bence only

the latter are presented in this report. Depending on whether SEPs change gradually or

abruptly across latent classes, the classes tan he respectively interpreted as pans ofthe

continuum or discrete, qualitatively ditTerent classes (McCutcheon, 1987). The relative

goodness-of-fit ofnested latent class models can he compared by a likelihood ratio 1: test

(McCutcheoD, 1987). While the use ofthis asymptotic chi-squared test is optimal when

expected cell counts are large, standard statistical method for sparse contingency tables is

not developed at present. The Akaike information criterion (AlC) was also used.

Exploratory latent class models, whereby all model parameters are estimated

without a priori restrictions, were fitted to 15 behavioral symptoms ofASPD and 12

behavioral symptoms ofCD (Table 1) in separate analyses using the LEM software

package for categorical data analysis (Vermunt, 1997). The LEM program uses the EM

algorithm to estimate latent class model parameters. The LCA ofCO symptoms was

performed to provide multivariate index for childhood behavior among ASPD symptom

based classes. We comPal'ed the relative fit of2· and 3 class models for ASPD or CD

symptoms in a sample of236 subjects (121 males and 115 females) who met OSM-IV

criteria for a1cohol dePendence in the past year, and showed a wide range ofsocial

adjustment. Geoder was included as a variable in the LCA. 80th 2 and 3-class models for

either ASPD or CD symptoms exhibited stable maximum likelihood solutions. Models

with more than 3 classes were not examined because the ftequency ofclass membership

in our moderate sample would decrease in the event ofa better model fi~ limiting the

125

•

ability ta examine further and interpret all classes. Usually, the structure investigated with

smaller data sets may he more complex than indicated even by the best-fitting model, and

large samples require more complex models to provide the best fit because they can

deteet smalt statistical effects which May, however, he oflittle practical importance

(Agresti, 1990). Therefore, interpretation oflatent classes need not always he based on

the absolute goodness-of-fit, but may consider the practical relevance ofrelative

goodness-of-fit in view ofpertinent knowledge (Bucholz et al. 1996). The 3-class

solutions in the present study provided the opportunity ta explore the latent structure of

antisocial behaviors in this manner.

Relationship ofLatent Classes to Alcoho/ism

Latent classes derived from ASPD symptoms were compared for extemal

variables relevant to alcoholism and described above. An overall association between

latent classification based on ASPD and CD symptoms was tested with the Pearson X2 test

for independence in a 3x3 contingency table. The linear association between CD and

ASPD symptom-based classes was tested using the Mantel-Haenszel X2 test for linear

association (Armitage & Berry, 1994). Due to unequal variances between classes, overall

tests across 3 ASPD symptom based classes for quantitative variables were done using

the X2 based Median test (Snedecor, 1956). Pair-wise comparisons between classes for

quantitative variables were done using the t-test, assuming equal or unequal variances as

determined by the 2-tailed f-test at the 0.05 significance level. Dichotomous variables

were generally tested using the Pearson 1: test, except where expeeted ftequencies

smaller than 5 were encountered; for these cases, Fisher's exact test was used. Most of

126

the pair-wise tests were performedpost hoc after the overall test was detennined to he

significant The exceptions were pair-wise comparisoDS for age, age ofonset ofalcohol

dependence, and proportion ofa1coholics first-degree relatives between male latent

classes characterized by non-aggressive and aggressive antisocial behaviors. These

comparisons were performed a priori because ofthe well-documented association of

violent behavior with male gender and Type 2 or highly heritable early onset alcoholism

(Virkkunen and Linnoila, 1997). In order to take into 8CCOWlt potential gender effects, ail

statistical tests were initially performed separately within the male and female subgroups.

Those variables that showed different results between gender categories are presented

separately for males and females, and remaining variables are presented in the pooled

sample.

A statistical examination ofmultiple latent classes necessitates multiple

comparisons. To reduce the inflation in the rate offalse positive results, we have limited

comparisons ofASPD symptom-based latent classes to several extemal variables deemed

MOst relevant from review ofthe literature as described in the variables section.

Furthennore, Many ofseleeted variables are correlated and hence the Bonferroni type

correction ofthe significance level would he too conservative. In this exploration we

opted to note ail results significant at the 2-tailed 0.05 level and discuss them in view of

relevant literature, referring to the 0.051evel as a tendency towards significance and 0.01

level as a significant difference.

127

•

RESULTS

AlI ofthe 121 male and 115 female subjects met DSM-IV criteria for alcohol

dependence in the past year. Most participants also met the DSM-IV criteria for alcohol

withdrawal (93% ofmales and 95% offemales) and alcohol abuse (86% ofmales and

79% offemales) in the past year. The DSM-m-R criteria for past alcohol dependence

(APA, 1987) were met by 89% ofmales (106/119) and 90% offemales (98/109). Male

and female subject groups were ofsimilar Mean age (males 36.1 yr, SD = 11.2; females

36.9 yr, SD = 11.9). The racial composition ofthe male and female groups was alsa

similar: predominantly white (94%), 2% black and 4% other. The distribution ofsocial

class based on the Hollingshead-Redlich index (Hollingshead & Redlich, 1958), recorded

in 106/121 males was 1-3%, II-Il%, m-270ÂI, IV-53%, and V-6%. Distribution ofmarital

status in males was 17% married, 12% living with a partner, 8% separated, 15%

divorced, and 49% never married. Similar distributions of social class and marital status

were observed in females.

LCA ofAdu/t Antisocial Behaviors

The latent 3-class model provided the best fit to the data on 15 symptoms of

ASPD in alcohol dependent males and females, among examined models (Table 3). The

observed Symptom Endorsement Probabilities (SEPs) in cach of3 latent classes are

graphically presented in Figure 1 (numerical values in the Appendix A). Class 1showed

either 0 or very low SEPs for ail symptoms, the highest being 0.07 for ubills'" and Unot

working" variables, and bence overall this class was tenned Socially Adjusted Adults

128

Table 3. LCA Model Fitting for ASPD Symptoms in Alcohol Dependenf

Males and Females

Madel -2 log-likelihood Ukelibood ratio 12 test

l-class 4377.26

p

2-class

3-class

3870.52

3675.79

506.74

194.73

17 (33 - 16) < 0.0000

10 (43 - 33) < 0.0000

-rndividuals who met OSM-IV criteria for alcobol dependence in the last 12 months. bNumber ofdegrees oftreedom equals the difference in the number ofparameters estimated by the n+1 class and the n-elass model;the number ofparameters estimated in the 3-c1ass model was reduced by the number ofconditionalprobabilities estimated at zero value (McCutcheon, 1987). The Aie aIso resulted in the 3-class solution.

129

0.0

..5 .6Eu~oe .4

UJESCo .2

~CI'.)

po

f

1 t

1

t1 ! l l~ 1 1.

0Class 1

(26.3%)

cClass2

(58.5%)

Class 3~

(15.2%)

Gender and Symptoms ofAntisocial Personality Disorder

Figure 1. Observed Gender and Symptom Endorsement Probabilities in ASPD Symptom

Based Latent Classes (N =236, 121 male, 115 female). Symbols (circles, squares, and

triangles) represent observed proportions of individuals who endorsed a particular

symptom in a given class. These observed symptom endorsement probabilities were very

similar to those estimated by the latent 3-class model, as noted in the methods section.

Horizontal reference lines are drawn at probabilities of0.25 and 0.75 for the sole purpose

ofvisual aid.

130

(SM). Relative to the SAA class, Class 2 bad higher SEPs for ail symptoms, the highest

SEPs in this class being for variables "absent from work" (0.55), "bills" (0.67) and "could

be anested" (0.52). While the SEPs for aU behaviors increased further in the Class 3, only

certain behaviors exlubited an abrupt increase ftom the Class 2 to Class 3. Specifically,

SEPs for variables "damage" and "weapon" increased from 0.05 and 0.04 in Class 2 to

0.47 and 0.42 in Class 3. The SEP for the variable "hurt person" increased from a low of

0.15 in the Class 2 to 0.58 in Class 3. Moreover, SEP for the variable "scam" a1so showed

an abrupt increase trom Class 2 (0.12) to Class 3 (0.92). In view ofthese SEP profiles,

Class 2 was termed Antisocial Non-Aggressive Adults (ANAA) and the Class 3 was

termed Antisocial Aggressive Adults (AAA). The frequencies oftheS~ ANAA and

AAA class were respectively 26% (62/236), 58% (138/236) and 15% (36/236). The SEP

values for male gender in the SM, ANAAA and AAA class were respectively 0.37, 0.56

and 0.58 (Appendix A). The rates ofalcoholics recruited from treatment (as opposed to

newspaper adds from the general population) in male SM, ANAA and AAA classes

were 87% (20/23), 71% (55/77), and 38% (8/21), respectively. Corresponding rates

among females were 44% (17/39), 26% (16/61), and 13% (2/15). These data in both

gender categories are consistent with the possibility that the most antisocial alcoholics

(MA c1ass) were less likely ta view their condition as socially undesirable and seek

treatmen~ instead being motivated to participate when otTered financial compensation.

LCA ofChildhood Antisocial Behaviors

The LCA ofCD symptoms~ conducted independently from the LCA ofASPD

symptoms, provided a multivariate index ofchildhood behavioral problems. Among the

131

•

examined models, a 3-class model again sbowed the best fit to 12 symptoms ofCD in

alcohol dependent males and females (Table 4). The highest SEPs observed in Class 1

were 0.15 and 0.18 for the behaviors "hook.y" and "lied" respectively (Figure 2,

numerical values for ail SEPs in the Appendix B). The SEPs for remaining bebavioral

symptoms ofconduct disorder in this class were either 0 or very low. The Class 1 overall

was hence similar ta the SAA class derived from ASPD symptoms, and was tenned

Socially Adjusted Children (SAC). As observed in the LCA ofASPD symptoms, the SEPs

for all symptoms were higher in each subsequent class. An abrupt increase in the SEP for

the variable "stole" was noted between the Class 1(O.OI) and either Class 2 or Class 3

(0.78 and 0.77 respectively). The variables "fights", "weapon" and "hurt persan" showed

an abrupt increase in SEPs between Class 2 (0.29, 0.08 and 0.15 respectively) and Class 3

(1,0.50, and 0.77 respectively). The SEPs for "damage" and, less frequent, "burt animal"

and "tire" symptoms also showed a greater iDcrease from Class 2 to Class 3 than from

Class 1 to Class 2. With respect ta the differences in SEPs for aggressive behaviors, these

two classes were broadly similar ta the ANAA and the AAA class derived from ASPD

symptoms. Therefore, Class 2 was termed Antisocial Non-Aggressive Children (ANAC)

and Class 3 was tenned Antisocial Aggressive Cbildren (AAC). The frequencies ofthe

SAC, ANAC and AAC class were respectively 45% (106/236), 46% (108/236) and 9%

(22/236). The SEP values for male gender in the SAC, ANAC and AAC class were

respectively 0.59,0.43 and 0.59.

132

Table 4. LCA Model Fitting for Conduet Disorder Symptoms in Alcohol Dependent

Males and Females

Madel -2 log-Iikelihood Likelihood ratio i test

l-class 3197.58

p

2-class

3-class

2737.55

2642.48

460.03

95.07

13 (26 - 13) < OOסס.0

8 (34 - 26) < OOסס.0

amdividuals who met OSM-IV criteria for alcohol dependence in the Iast 12 months. 'Number ofdegrees offteedom equals the difference in the number ofparameters estimated by the n+1 class and the n-class Madel;the number ofparameters estimated in the 2 and 3-c1155 models was reduced by the number ofconditionalprobabilities estimated at zero value. The Ale also resulted in the 3-class solution.

133

0Class 1

(44.901'0)

0Class 2

(45.8%)

.:. Class 3

(9.3%)

.l1

l(

j

1

( >0 ~

--.- --.-

·~- .8:Eas.&Je

Q..- .6clUelU~..0"0 .4c~

egc. .2e>.

ri)

0.0

1.0

Gender and Symptoms ofConduct Disorder

Figure 2. Observed Gender and Symptom Endorsement Probabilities in CD Symptom

Based Latent Classes (N = 236, 121 male, 115 female). The meaning ofsymbols is

explained in Figure 1.

134

Cross-tabulation ofAdult and Childhood Latent Classes

Cross-tabulation ofthe independently obtained latent 3-ciass solutions for

antisocial bebaviors after (ASPD) and before (CD) lSyr ofage, stratified by gender, is

shown in Table S. As might have been expeded, in bath male and female individuals

there was a significant overall association between these latent classifications. However,

only among females was there a significant linear association between adult and

childhood behavioral classes. The lack ofIinear association in males was main]y due to

the fact that most males in the adult ANAA elass (52%) belonged ta the SAC c1ass in

ehildhood (Table 5). Ofthese 40 males, 60% (24/40) had at least one behavioral

symptom ofconduet disorder. More than halfofmembers ofthe AAA class in elther

males or females did not belong to the analogous childhood AAC class, probabl~· due to

the small total number of individuals in the AAC class (Table 5).

Phenomenology ofAlcoholism in the SAA. ANAA and the MA C/ass

We compared adult latent classes for age, age ofonset for alcohol dependcnce.

and frequency ofalcoholic first-degree relatives. For all ofthese variables. difTerent

results were obtained in male and female subgroups and therefore results are presenled

separately by gender.

Tables 6 and 7 present comparisons ofthe SAA, ANAA and AAA class for age

and age ofonset for alcohol dependence, in alcohol dependent males and females

respectively. Age and age ofonset for alcohol dependence showed significant overall

association with latent classification in both males and females~ however the pattern of

ditTerentiation between latent classes within gender categories was somewhat different.

135

Table S. Cross-tabulation ofASPD and CD Symptom Based Latent Classes

Stratified by Gender

Percent (N) of Subjects in

ASPD Latent CI,,'''· (>1Syr)

Gender CD Latent Classes «15yr) SAA ANAA AAA X2 df p

Male SAC 83 (19) 52(40) 14(3)

ANAC 17 (4) 43 (33) 43 (9) 38.03b 4 < 0.0001

AAC 0(0) 5 (4) 43 (9) 3.421: 0.064

Female SAC 74 (29) 2S (15) 0(0)

ANAC 23 (9) 70(43) 67 (10) 46.9Sb 4 <0.0001

MC 3 (1) S (3) 33 (5) 22.901: <0.0001

·Symbols: SAA, Socially Adjusted Adults; AN~ Antisocial Non-Aggressive AduJts; AM.. AntisocialAggressive Adults; SAC, Socially Adjusted Children; ANAC. Antisocial Non-Aggressive Children; AAC,Antisocial Aggressive Children. bpearson X2 test for independence in the presented lx3 contingency table. 2-taiIed. 'Mantel-Haenszel X2 test for linear association between ASPD and CD latent classes, 2..tailed.

136

e

Table 6. Comparison ofLatent Classes Derived from ASPD Symptoms: Alcohol Dependentl Males

e

Variable

SAA

(N = 23)

ANAA

(N = 77)

AAA

(N = 21) Overall Test Statistic

n Mean sn n Mean sn n Mean sn x'1. df p

Age

Age of Onset for

23 39.74" 11.89 76 37.I3-c 10.87 20 26.9C 4.94 16.41 2 < 0.001

AJcohol Dependence 22 28.32" 8.32 71 25.2111.C 7.26 20 19.15e' 3.48 13.19 2 0.001

Due to unequal variances between groups. overall comparisons for quantitative variables were made with the non-parametric X2based median test. Pair..wisequantitative comparisons were made using the 2-tailed t..tests at the O.OS significance level. assuming equal or unequal variance as determined by the F tests at the0.05 significance level. For these pair..wise comparisons. in each group where applicable subjects outside of2SD trom the mean were excluded. Identical super..'script in a descriptive statistic for any two latent classes for a given variable denotes pair..wise comparison. Bold superscripts denote a priori pair..wise tests.performed before the overall test across 3 classes. Symbols: 81ndividuals who met DSM-IV criteria for alcohol dependence within the last 12 months. "Latentclasses: SM Socially Adjusted Adults; ANM Antisocial Non..Aggressive Adults;~ Antisocial Agressive Adults. "not significant at the 2..tailed 0.05 level.e'p < 0.001. t..test. 2-tailed.

137

e

T.ble 7. Comparison oC Latent Classes Derived from ASPD Symptoms: Alcohol Dependent· Females

e

Variable

Age

Age of ORset for

Latent Classb

SAA ANAA AAA

(N =39) (N =61) (N = 15) Overall Test Statistic

n Mean SO n Mean SD n Mean SD x2 df P

37 44.05c 10.75 61 33.9c,- 10.87 IS 33.93- 8.14 13.38 2 0.001

)UcoholDependence 34 31.21c 9.43 S6 22.75c•d 6.75 14 19.0~ 5.03 14.46 2 0.001

Statistical testing was performed as described in Table 6. Identical super-script in a descriptive statistic for any two latent classes for a given variable denotes pair­wise comparison. Symbols: Ilndividuals who met OSM-IV criteria for alcohol dependence within the last 12 months. butent classes: SM Socially AdjustedAdults~ ANM Antisocial Non-Aggressive Adults~ MA, Antisocial Aggressive Adults. Rlnot significant at the 2-tailed O.05level. cp < 0.001, t-test, 2-tailed;dp =0.027, non-parametric Mann-Whitney U test. 2-tailed (the t-test was influenced by non-nonnal distribution in the AM clus).

138

•

In males, the AAA class was younger and bad the carlier age ofonset ofalcohol

dependence (Table 6). As noted previously, in males 52% ofindividuals ftom the ANAA

class were members ofthe childhood SAC class, contnbuting ta the lack oflinear

association between childhood and adult classes. To investigate these individuals further,

we examined the ANAA class after stratification iota those who were members ofthe

childhood SAC class, N = 40, and the remainder, N = 37. The former subgroup was more

similar to the SAA class: the Mean age was 40.9 yr, SO = 10.8, and the Mean age ofonset

for alcohol dependence was 29.3 yr, SO =9.7. The latter subgroup had the Mean age of

33.7 yr, SO = 10.3, and the Mean age ofonset for alcohol dependence of24.2 yr, SO =

8.2. In females, but not males, the ANAA class was younger and had the earlier age of

onset ofalcohol dependence as compared to the SAA class (Table 7). A small nomber of

females from the AAA class showed a tendency (p < 0.05) towards lower age ofonset for

alcohol dependence than the ANAA class, notwithstanding similar corrent age (Table 7).

The respective proportions ofmales from the SM, ANAA and the MA class

who completed the FR report regarding first-degree relatives were 12/23,58/77 and

16/21. The frequencies ofalcoholic first-degree relatives ofmales from the SAA, ANAA,

and the AAA class were 0.31, (27/86), 0.26 (90/341) and 0.41 (23/56). There was no

significant overa11 association between the frequency ofalcoholism in first-degree

relatives and ASPD symptom based latent classification <X2 = 5.33, df= 2, p =0.07,2·

tailed). Ali ofthe 12/23 males from the SAA class who completed the FH report had at

least one alcoholic first.degree relative, and therefore the FH report for the SAA class is

biased towards higher frequency ofalcoholic relatives, contributing to the lack of

significant overall association. However, apriori comparison ofthe ANAA and the AAA

139

class showed a tendency towards a greater ftequency ofalcoholism among first-degree

relatives ofmales ftom the AM class (X2=5.09, df= 1, P = 0.024, 2-ta11ed).

The respective proportions offemales ftom the SAA, ANAA and the AAA class

who completed the FH report were 28139, 43/61, and 13/15. The frequencies ofalcoholic

first-degree relatives offemales trom these classes were respectively 0.27 (421158), 0.38

(73/193) and 0.44 (30/68). Overall, there was a tendency towards a significant association

between the ftequency ofa1coholism in first-degree relatives and latent classification (1..2

= 8.10, df= 2, P =0.017, 2-tailed). The increase in the ftequencyofalcoholic first-degree

relatives between the SM and the ANAA class approached significanœ <'1.2 = 4.98, df=

l, P= 0.026, 2-tailed); there was no significant difference between the ANAA class and

the small AAA class in this respect <1..2 = 0.83, df= 1, P = 0.36, 2-tailed).

Psychopathology in the SM, ANM, and the MA C/ass

Table 8 presents psychopathology in latent classes derived from ASPD symptoms.

Similar statistical results were obtained within gender categories and in the pooled

sample, and therefore only the pooled sample is presented. The strong association with

membership in the childhood MC class further supports distinct character ofthe AAA

class, which is not apparent when only the count of3 or more CD symptoms is

considered (Table 8). The frequency ofdrug use behavior increased progressively across

latent classes. Depression and anxiety were not significantly associated with the present

latent classification, suggesting that these factors do not account for observed differences

between latent classes. The overall proportions ofmales and females with lifctime

depression were respectively 40% and 57%, and overall proportions ofthose with anxiety

140

Table 8. Psychiatrie Co-morbidity in ASPD Symptom Based Latent Classes

Perœnt (N) of Subjects in

ASPP Latent a,,'O· (>1Sm

Variable

SAA

(N = 62)

ANAA

(N= 138)

AAA

(N=36) df

CD 3+ symptoms 19 (12) 54 (74) 89 (32) _c

AAC d 2 (1)- 5 (7)fa.e 39 {14t 44.54 2 <0.001

DrugUsl 31 (19)' 67 (92r 100 (36)b 49.35 2 <0.001

Lifetime Depression S5 (34) 43 (60) 53 (l9) 2.62 2 0.27

80ugbt Help for Anxiety 31 (19) 32 (44) 47 (l1) 3.40 2 0.18

AlI statistical tests used ratios '''yeslno'' and were initially performed in males and females separately withresuJts similar to those presented here in the pooled sample. Identical superscript for any two latent classesfor a given variable indicates pairwise comparison, performed after the significant overall test. lLatentcla.;ses: SAA, Socially Adjusted Adults; ANAA, Antisocial Non-Aggressive Adults; AM AntisocialAggressive Adults. bpearson X2 test ofindependence in 2x3 contingency table (variable yes/no x latentclassification). cnus variable is shown for descriptive purposes. dAntisocial Aggressive Children from theLCA ofCD symptoms. "not significant at the 2-tailed O.OS leve~ FlSher's exact test. cp < 0.001, Fisher'sexact t~ 2-tailed; fUsed drogs in the last 30 days and/or had lifetime problems with drugs. 'x2 = 22.48. df=l, P < 0.001, 2-tailed; bX:Z = 16.3, df= l, P < 0.001, 2-tailed.

141

were 21% and 47010 respectively. This is consistent with higher prevalence ofthese

disorders in alcoholic women (De1Boca, 1994).

DISCUSSION

The latent class analysis ofASPD symptoms (behaviors after 15 yr ofage) among

alcohol-dependent individuals, showing a wide range ofsocial adjustment, provided

evidence for 3 qualitative behavioral classes [Socially Adjusted Adults (SAA. N =62.

37% males), Antisocial Non-Aggressive Adults (ANAA, N = 138,56% males), and

Antisocial Aggressive Adults (AM, N = 36,58% males)], ratherthan continuous

variation along the severity dimension. Male and female subgroups were similar "1th

respect to size, demographic characteristics and present and past diagnoses ofalcohol ism.

The increased proportion ofmales in the ANAA and the AAA class is consistent Wlth the

well-established higher prevalence ofASPD in alcoholic males (Hesselbrock et al 1984:

Babor et al. (992). Failure to find a Iinear association between analogous. independently

obtained childhood « 15 yr) and adult classes was observed only in males. and 15

discussed below in greater detail.

While the AAA class showed higher symptom endorsement probabilitles (SEPs)

for ail antisocial behaviors than did the ANAA class, the endorsement ofoven a~'1'e5sive

behaviors increased abruptly, suggesting that aggressive behaviors may he substanuvely

independent from other antisocial behaviors. An abrupt increase in the endorsement of

certain behaviors is more consistent with the presence ofqualitative ditTerences between

classes rather than purely continuous variation (McCutcheon, 1987). The distinctive

142

character ofthe MA class is further supported by the strong association with

membership in the aggressive childhood (AAC) class, in agreement with the DSM-IV

recognition ofthe aggressive early onset subtype ofCD (APA, 1994). These tindings are

consistent with the view that aggressive bebavior may he an important indicator of

heterogeneity within the ASPD diagnostic category (Byudens-Branchey et al. 1989;

Loeher, 1990; Sher and Trull, 1994). In addition, the endorsement ofscamming bebavior

also increased abruptly from the ANAA to the MA class, suggesting some commonality

between this trait and overt aggressive behaviors. The ANAA class had the greatest

endorsement for being repeatedly absent from work for no good reason, regularly failing

to pay bills, and exhtbiting behaviors that are grounds for arrest. The antisocial latent

classes obtained might therefore also he interpreted to be largely congruent with the

DSM-IV ASPD criterion of"consistent irresponsibility" for the ANAA class, and most of

the DSM-IV ASPD criteria including "irritability and aggressiveness" and "deceitfulness"

for the AAA class (APA, 1994).

To our knowledge, the present study is the first to ask whether there were

subtypes ofalcohol-dependent individuals based on the LCA ofspecific sytnptom data

for ASPD. The recent LCA ofASPD symptoms conducted in the COGA sample asked

different questions, including whether there are subtypes ofASPD, and whether specific

s}'mptom patterns are associated with alcohol dependence (Bucholz et al. 2000). The

COGA population, which was analyzed, comprised high-risk alcoholic probands

identified from treatment (19.4%), their biological relatives (71.1%), and controls (9.5%).

The COGA sample is not representative, which limited the generalizability ofthe results

(Bucholz et al. 2000). Moreover, inclusion offamily members in the LCA could

143

presumablyobscure potential distinction between probands, thus introducing a bias

towards the concluded continuum ofseverity for ASPD symptoms. Because the latent

structure ofASPD symptoIDS among alcohol-dependent individuals is not necessarily the

same as in other populations, the differences in questions posed and populations analyzed

limit the comparison ofthe present latent class solution with that presented in the COGA

study. Nevertheless, it is ofinterest ta note that the COGA male class D bas a mild

childhood behavioral profile, but an antisocial adult profile, and is thus similar to the late

onset subgroup ofmales from the ANAA class in the present report Although this

subgroup ofANAA males showed milder childhood and adult behavioral profiles than

did the COGA class D, both results support the nosological separation ofchildhood and

adult antisocial behaviors. The category ofprimarily adult antisocial behavior is not an

unexpected finding in populations with substantial substance abuse (Cottier et al. 1995),

due to the negative impact of this behavior on social adjustment.

Compared to the LCA oftemperance board registrations in male twins that

included drunkenness, drunken driving and crime (Kendler et al. 1998), the slodies cited

above used bath males and females and a richer range ofbehavioral infonnation. Kendler

and colleagues found evidence for qualitative latent classes, as did the present study. The

LCA ofsymptoms ofalcohol dependence in the COGA sample ofrelatives produced a

continuum ofseverity (Bucholz, 1996). The exception was the most severe class 4,

which was characterized by withdrawal syndrome as per OSM-ill-R criteria for

withdrawal, requiring shakes and one other withdrawal symptom (Bucholz, 1996).

Almost all ofpresent subjects displayed a1cohol withdrawal by OSM-IV criteria, which

144

•

•

do not obligatorily require shaking (APA, 1994). These subjects might therefore ditTer

somewbat ftom the class 4 subjects in the COGA population.

In the present study, adult behaviorallatent classes were validated in relation ta

alcoholism by contrasting variables that were not iDCluded in the LCA. Barly onset

alcoholism is associated with antisocial behavior in both males and females, and is alsa

characterized by a lower age ofonset for a1cohol dePendence, more frequent and

aggressive problem behaviors in childhood, increased drug use, and an increased

frequency ofalcoholic first-degree relatives (Cloninger et al. 1981; Penick et al. 1984.

Hesselbrock et al. 1984; Cloninger 1995; Scbuckit,.1985; Hesselbrock et al. 1985. Glenn

and Nixon, 1991; Bahor et al. 1992; McGue et al. 1997; Kendler et al. 1998). In bath

males and females, the AAA class had the cbaracteristics ofthe early onset alcohol tsm.

while the SAA class had the characteristics ofthe late onset alcoholism. Current age dld

not account for other charaeteristics ofearly onset alcoholism in sorne studies (Babor ct

al. 1992; McGue et al. 1997), and there was insufficient statistical power for analysas

stratified by corrent age in the present study. Although there is heterogeneity ln the

criteria used by different investigators to identify early and late onset alcoholics. the

intensely studied sample ofFinnish male aggressive alcoholics is similar in many respects

to the male AAA class identified in the present report (Virkkunen and Linnoila. 1997)

The present exploration could therefore he interpreted as providing sorne addluonal

support for the utility ofthis Finnish subgroup in alcohol research. ln females. bUI nol in

males, the ANAA class aiso displayed an early anset aicoholism in cornparison to the

SAA class~ although to the less extreme extent than the AAA class. ln males~ rnembers of

the ANAA who belonged to the sociaUy adjusted chiidhood class had the late onset of

145

•

•

alcohol dependence, presumably in part mediating exhibited adult antisocial behavior,

while the remaioing ANAA males had intermediate onset. This is consistent with

longitudinal studies linking childhood antisocial behavior ta an earlier onset of

alcoholism (Jessor and Jessor, 1975; Cloninger et al. 1988). The facilitation ofantisocial

behavior by drinking could contribute to documented higher frequency ofthese behaviors

in male alcoholics, noted before, and the overrepresentation ofmales in treatment, as the

rate ofASPD is higher among alcoholics ascertained from tteatment (Waldman and

Slutske, 2000).

There are a number of limitations to the present study. Although collected using a

carefully prepared interview instrumen~ the data represent self-reports rather than

objective measures and have substantial retrospective charaeter. The sampling ofequally

represented age, drinking and gender categories in the WHO-ISBRA project might have

influenced the generalizability of results. The family history report was not completed by

aIl subjects. The population was predominantly white, providing little information

pertaining to other races. The moderate total sample size required that a joint LCA of

males and femaIes he condueted, including gender as a variable, in order to accommodate

a relatively large number ofanalyzed symptoms, and bas limited comparative analysis to

3 latent classes. The total sample size, however, is comparable to that used in the bulk of

alcoholism research to date, hence the observed variation could perhaps he MOst readily

related to accumulated knowledge. The size of latent classes, particularly the AAA class,

decreased after stratification by gender. Nevertheless, we deemed it useful to retain the

AAA class because of important features (i.e., aggressive behaviors), distinguishing these

subjects from the socially maladjusted subjects in the ANAA class. In view ofstatistical

146

power, we were only able to use those secondary variables deemed highly relevant to

validate latent classes in relation ta subtypes ofalcoholism reported by others, rather than

perform more extensive exploratory analyses. Moreover, multivariate analyses with a

single data set provide a broader margin for statistical artifacts. Tbese limitations

underline the requirement for the replication ofthe PreSent LCA solution in an

independent sample.

In conclusion., the present empirical analysis identified discontinuous latent

classes in a broadly ascertained sample ofalcohol-dependent individuals, evaluated from

a multidimensional behavioral perspective. These potential discontinuities MaY he of

particular interest for genetic mapping studies, which are currently focused around the

concept ofearly onset antisocial alcoholism (parsian 1999; Nielsen et al. 1998;

Lappalainen et al. 1998). In future studies, attention to patterns ofalcohol consumption

and to genetically intluenced personality and character traits that May constitute risk

factors common to antisociality and alcoholism, [e.g., behavioral disinlubition., novelty

seeking, uncooperativeness, etc. (Cloninger, 1987; Sher and Trull, 1994; Cloninger, 1995;

Howard et al. 1997; Waldman and Slutske, 2000)], as weil as to other symptoms of

psychopathology, cao provide better insight ioto the phenotypes suggested in the present

exploration. It will he possible to address some ofthese issues, as weIl as sorne of present

limitations, in the large international WHO/ISBRA sample (n - 3000), ofwhich alcohol

dependent subjects from the Montreal centre studied here are a part. However, an

independent replication study in a representative sample ofalcobol dependent individuals

is needed to confinn the present findings.

147

Appendix A. Symptom Endorsement Probabilities Observed in Latent Classes ofAlcohol

Dependent Individuals Derived ftom Behavioral Symptoms ofASPD

(After 15yr ofAge)

Symptom SAA- ~ AAA

N=62 N=138 N=36

male gender 0.37 0.56 0.58

Dot working 0.07 0.34 0.92

absent from work 0.06 0.55 0.83

quit job 0 0.23 0.72

traveled 0 0.40 0.72

no home 0 0.28 0.44

lied 0.02 0.48 0.89

bills 0.07 0.67 0.94

stole 0.02 0.28 0.83

damage 0 0.05 0.47

hurt persan 0.02 0.15 0.58

weapon 0 0.04 0.42

scam 0 0.12 0.92

unfaithful 0.03 0.32 0.58

arrest 0.05 0.30 0.83

could be arrested 0 0.52 0.97

-Utent classes:S~ Socially Adjusted Adults; ANAA. Antisocial Non-Aggressive Adults; AMAntisocial Aggressive Adults. Behavioral symptoms ofASPD are descnDed more extensively in Table 1.

148

AppeDdiI B. Symptom Endorsement Probabilities Observed in Latent Classes ofAlcohol

Dependent Individuals Derived from Behavioral Symptoms ofCD

(Before ISyr ofAge)

Symptom SAC- ANAC MC

N== 106 N= 108 N=22

malegender 0.59 0.43 0.59

hooky 0.15 0.74

suspended o.os 0.44

runaway 0.07 0.40 0.68

lied 0.18 0.75

$laie 0.01 0.78 0.77

damage 0.04 0.28 0.86

fights 0.04 0.29

weapon 0 0.08 0.50

hurt person 0 0.15 0.77

hurt animal 0.01 0.07 0.27

tire 0 0.08 0.26

arrest 0.01 0.35 0.77

-Latent classes: SAC, Socially Adjusted Children; ANAC, Antisocial Non-Aggressive Children; AAC,Antisocial Aggressive Children. Behavioral symptoms ofconduet disorder are described more extensively inTable 1.

149

BridgiDg CommeDary

Regarding the preœding manuscri~ a very recent report including latent class

analysis ofantisocial behaviors in the sample of7326 male and fernale subjects from the

National Longitudinal Survey ofYouth (Muthen &. Muthe~ 2000) may be relevant. The

analysis identified 4 classes, in which SEPs for "tÏghting" were 0.09, 0.53, 0.20, and 0.74,

trom class 1 to 4 respectively. Because the SEPs did not increase gradually aeross classes

as they did for sorne other symptoms, e.g. shoplifting, the authors suggest that the results

May ref1ect different kinds ofantisocial behaviors, rather than a single dimension of

increasing severity. However, the differences between the population anaIyzed in this

paper, and our own population, preclude direct comparison ofthese results with the study

presented here.

In view ofthe frequent use ofbasic latent class analysis with likelihood ratio

testing to evaluate the number of latent classes in psychiatrie research, for instance

Bucholz et al. (1996) or Sullivan et al. (1998), it is of interest to note pertinent views

from the perspective ofstatistical theory. White latent class models cao he viewed as

nested models, they are nested in a way that does not meet certain assumptions ofthe

likelihood ratio test statistics (Vermunt, 1997a; Uebersax, 2000). Rather, the use ofmore

"heuristic" approaches, such as the model parsimony measure Akaike Information

Criterion (AIC), is more appropriate (Uebersax, 2000). In the present study, the AIC,

calculated as -2 log likelihood plus 2 tintes the number ofparameters, resulted in the

latent 3-class solutions as did the likelihood ratio test: the AIC value decreased from the

150

l-class to 3-class solution for both the ASPD and CD symptom based analyses. An

alternative, computation...intensive approach involves simulation ofdata sets by Monte

Carlo, bootstrapping, or sunilar methods (Aitken et al. 1981; Langeheine et al 1996).

Rejection ofmodels in which sorne latent classes have low prevalences, which is often

necessary to allow interpretation of latent classes, cao also he viewed as a criterion for

model selection (Uebersax, 2000). This often occurs when a relatively large number of

indicator variables (symptoms) are analyzed in a comparatively small sample, as is the

case in the present study or the study ofBucholz et. al. (1996). In addition to removing

indicators ofvery small frequency, as was done in the present study, another option for

improved overall model fitting might he to remove indicators that are conceptually

redundant. However, this would invariably involve a degree ofarbitrariness, because a set

ofad hoc criteria for redundancy would need to he devised in the absence offonnal rules.

For a complex behavioral disorder ofunknown. etiology, it is particularly difficult to

decide which symptoms to retain. Indee~ one ofthe important goals is to identify

relationships between symptoms that might not he self-evident. Additionally, like any

other classification, modal classification (assignment of individuals to the MOst probable

latent class membership) is subject to some enar; here this occurs because ofnon-zero

probabilities for alternative class membership. In the present study, the expeeted

proportion ofclassification errors due to modal assignment (Vermunt, 1997) for the LCA

ofASPD symptoms was -0.05, and -0.04 for the LCA ofCD symptoms.

The present, exploratory latent class analysis specifically examined whether

variation in symptom patterns can he viewed as continuous or discrete in arder ta infonn

genetic studies in this particular regard, and it is therefore a descriptive study. More

151

elaborate~ explanatory questions can also he examined in multivariate categorical data

sets. Where this is the~ a study design can include a derivation ofthe meaningful

explanatory hypothesis prior to testing it in multivariate models; alternatively, the study

May generate an explanatory hypothesis from the multivariate analysis. Multivariate

hypothesis-generating design may be a valuable option for complex disorders in

particular, where simple research designs may he poorly suited to capture underlying

complex relationships. Sorne madeling possibilities include using gender as a grouping

variable to examine causal hypotheses, using properly justified a priori model restrictions

rather than exploratory estimation ofail parameters, and simultaneously USiDg separate

latent variables for childhood and adult symptoms where data cao support the iDCrease in

the number ofparameters. For example, the logliDear modeling capabilities ofthe LEM

software allow for direct modeling of latent class parameters and the use oflatent classes

as response or predictor variables, without the use ofmodal classification (Vermun~

1997). A major statistical development that allowed examination ofnumerous

explanatory hypotheses, enabling incorporation ofexternal variables into causal models

with categoricallatent variables, was a "modified LISREL approach" (Hagenaars, 1993).

This method is named after the LISREL model that brings together factor analysis and

regression analysis into one structural model for continuous data. Presentation of

structural-modeling techniques is outside ofthe scope ofthis wor~ but is explicated in

the references herein, particularly Hagenaars (1993), and Uebersax (2000) for cunent

developments in latent class modeling, and additionalliterature.

152

The following manuscript is based on the data from to Collaborative Research

Group on Genetics ofAlcoholism (COGA), wbich were distributed ta participants orthe

Genetic Analysis Workshop (GAW) Il, held in Arcacho~France, 1998. The GAW is

held at regular interva1s with the goal ofaddressing methodological issues in genetic

epidemiology. On each occasion a different theme is chosen, with an appropriate

simulated or real data set to stimulate participants contributions.

The manuscript explores the eifect ofstratification into early- and late-onset

subgroups ofalcoholics on results from the initial genome scan. It is not directly related

to the preceding manuscript, except that the early-onset subgroup is likely to have

charaeteristics sunilar to those round in the socially maladjusted classes. Agam, because

comparable data are not available, precise comparisons cannot he made.

In addition, this manuscript explores the impact ofphenotype definition that

includes either alcoholism or smoking, or both, in the '~affeeted" category. Besides ather

substance abuse, a strong association exists between alcoholism and smoking. The

incidence ofsmoking among alcoholics in treatment often exceeds 70% (Bobo, 1992;

Gulliver et al. 2000). The population prevalence ofsmoking is declining (Bobo, 1992;

Bergen & Caporaso, 1999), and the 1987 National Health Survey suggested prevalences

of31.7% for men and 26.8% for women in the United States (Fiore et al. (989). Twin

studies document genetic influences on smoking behavior in bath genders, with

heritability ofabout 50% (reviewed in Rossin& 1998). Twin studies have also suggested

presence ofgenetic factors common to alcoholism and smoking (Swan et al. 1996; True

et al. 1999). This finding is weil supported by extensive human and animalliterature

documenting commonality in physiologjcal pathways ofaddictions to different

153

substances ofabuse; i.e. the activation ofthe dopaminergic mesolimbic pathwayand the

increase in brain dopamine levels are reward mecbanisms common to alcobol7 nicotine7

cocaine7 amphetamines (reviewed in Koob7 2000). However, the researcb interest in the

genetics ofsmoking bas lagged behind the interest in the genetics ofalcoholism

(Kozlowski, 1991). There are some controversial reports about the potential role ofthe

dopamine DRD2 receptor gene variants in smoking (Bierut et al. 2000; Spitz et al. 1998).

Potential candidate genes for smoking are reviewed by Rossing (1998)7 and Many of

those are also candidates for alcohol related phenotypes.

The following is a description ofthe COGA data set relevant to the present

manuscri~ which was provided by COGA investigators to participants ofthe GAWI1 7

and May help familiarize the reader with the study background

"Description ofCOGA Data for GAW Il:

The Collaborative Study on the Genetics ofAlcobolism (COGA) is a six--center

program to identify and map genes that increase susceptlbility to develop Alcohol

Dependence and related phenotypes. In order to ascertain infonnative families for the

study ofgenetic linkage, approximately 1261 probands with alcohol dependence were

selected from inpatient and outpatient treatment units. Families were required to have

three or more available sibs (including the proband) ifboth parents were a1so available.

Four or more sibs were required ifone or both parents were missing or unavailable. The

proband could belong either to the otIspring or parental generation. At least two relatives

were required to live in the catchment area ofa COGA center. Probands were not

included in the study ifthey were uncooperative, were positive for the mv virus, were

intravenous drug users, had a fatal iUness or were unable to participate in the protocol.

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•

•

First-degree relatives were personally interviewed and administered a personality trait

inventory (N-8996 adult interviews) and families with three or more affected members

(alcohol dependence) were selected for genetic linkage studies. Bilineal families were not

included Children age seven and older were interviewed (N-1309) as weil as adults.

Nuclear families were extended either by ascertaining second and third-degree

relatives through affected members ofthe primary family or by leapfrogging over an

unaffected individual into a branch ofthe family tbat included affected members

(ascertained by history). Members ofthe extended branches ofthe families were

measured with the same protoeol that was used to cbaracterize the densely atTected

nuclear families. Bilineal branches were not ascertained

The data set to he distnbuted for GAWll ineludes 105 pedigrees with 1214

members. Nine...hundred and ninety-two members have been genotyped and ofthese 970

have been interviewed using the adult assessment protoeol. A subset ofthe interviewed

adults (813) also successfully completed the personality trait assessment. Twenty-two

individuals have been genotyped and did not receive the adult assessment protocol and 13

individuals have been assessed but were not genotyped. Six hundred and seven

individuals in103 families were assessed in COGA neurophysiology laboratories.

Two hundred and ninety-six markers, with average heterozygosity of0.73, have

been typed at an average intermarker distance of 13.6 centimorgans. Allele frequencies

have been estimated with the USER MI3 program (M. Boenke) and the program

CRIMAP (p. Green) bas been used ta estimate marker arder and distances. The affected

status ofAlcohol Dependence requires a positive diagnosis ofAlcohol DePendence by

the DSM m-R criteria ofthe American Psychiatrie Association and definite Alcoholism

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by the Feighner Criteria This is referred to as the COOA criterion for alcohol

dependence.

A semi-structured interview for the lifetime assessment ofpsychiatric and alcohol

related psychopatbology was developed for this program. The SSAGA (Semi-Structured

Interview for the Assessment ofthe Genetics ofAlcoholism) makes diagnoses in multiple

diagnostic systems, assesses alcohol consumptio~ enquires about hannful use ofalcohol

and enables age-at-onset to he measured. Lifetime cigarette smoking is also measured. A

test-retest reliability study conducted betwecn and within COGA sites attested to the

reliability ofthe lifetime diagnosis ofalcohol dependence.

Personality traits are assessed with the Tridimensional Personality Questionnaire

(TPQ) developed by Cloninger and associates. It bas been found to he heritable and its

scales have been correlated with the lifetime diagnosis ofalcohol dependencc.

There are 228 independently counted alcohol dependent affected sibpans ID these

data using COGA criteria. Individuals are categorized as unaffected if they dnnk but have

no symptoms ofalcohol dependence or abuse (Number of unaffected sibpairs = 30)

The Collaborative Study on the Genetics ofAlcoholism (COGA) (H. Beglelter~

SUNY HSCB, Principal Investigator, T. Reich, Washington University~ Co-Princlpal

Investigator) includes six ditferent ecnters where data collection takes place. The six

sites and Principal Investigator and Co-Investigators are: Indiana University (l

Numherger Jr., T.-K. Li, P.M. Conneally, H. Edenberg); University of Iowa (R. Crowe9

S. Kuperman); University ofCalifornia at San Diego and Scripps Institute (M. Schuckit't

F. Bloom); University ofConnecticut (V. Hesselbrock); State University ofNew Yor~

Health Sciences Center at Brooklyn (B. Porjesz, H. Begleiter); Washington University in

156

St Louis (T. Reic~ C.R. Cloninger, J. Rice). This national collaborative study is

supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) by

U.S.P.H.S. grants NIAAA UIOAA08401, UIOAA0S402, UIOAA08403."

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3(b). EXPLORING THE IMPACf OF EXTENDED PHENOTYPE

IN STRAID1ED SAMPLES

Aeknowledgement

The following manuscript, entitled "Exploring the Impact ofExtended Phenotype

in Stratified Samples" by Dija Kovac, Eric Rouillard, Dr. Chantal Mérette, and Dr.

Robena Palmour, is published in the journal Genetic Epidemiology 17(Suppl 1): S211­

8216, 1999. Copyright © (1999 Wiley-Liss, IDe.). Reprinted by permission ofWiley-Liss,

me., a subsidiary ofJohn Wiley &. Sons, Ine.

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