Supplementary documents
Contents
Protocol and search terms
Quality Assessment Tool
Screening checklist
Data collection template
PRISMA Checklist
Table of quality assessment scores for included studies
Results for separate emotions
Results from meta-regression
Forrest plot for neutral valence meta-analysis
Page number
2
5
6
7
8
10
11
20
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1
Protocol and search terms
Review question
The aim of this systematic review is to examine the relationship between genetic risk for schizophrenia (based on molecular genetics or family history) and cognitive biases that are associated with psychosis.
Searches
EMBASE, MEDLINE, MEDLINE-in-process, PSYCHinfo will be searched from the beginning of their records up to the present date using the keyword search terms listed below.
Hand searches will be conducted of reference sections of eligible studies.
Searches will be made using the following search terms:
Genetic high risk: polygenic OR “risk profile score” OR gene* AND (risk OR liability OR susceptib* OR predispos*) OR “high risk”
Family history high risk: “first degree relati*” OR “famil* risk”
Schizophrenia: Schizoph* OR psychosis OR psychotic OR hallucinat* OR delusion* OR paranoi* OR schizoaffective OR schizotypy
Cognintive bias: (bias* OR deficit OR reason*) AND (cognition OR cognitive OR meta cog* OR metacog* OR attention* OR process* OR perceptual OR information processing OR perception)
Source Monitoring: (source OR reality OR self OR external) AND (memory OR monitoring OR recognition) OR “self generated speech” OR “external misattribut*” OR “externali* bias”
Jumping to Conclusions bias: jump* adj2 conclusion* OR “data gathering” OR beads adj2 task OR “probability reas*”
External attribution bias: “external attribut*” “internal attribut*” OR “Locus of control” OR “attribut* style”
Top-down processing: “Top-down processing” OR “top down processing” OR “auditory feedback” OR “visual feedback”
Belief inflexibility: “belief inflex*” OR “belief flex*” OR BADE OR disconfirm* adj2 bias OR “evidence integrat*”
Emotion recognition: (emotion* OR affect* OR facial) AND (recogni* OR perception OR perceive OR process*)
The final search term structure will be:
High risk (genetics/family history) AND Schizophrenia AND one of cognitive/perceptual biases
2
Types of study to be included
Any study design that includes a comparison between participants and control groups.
Condition or domain being studied
Cognitive biases
Participants/population
General population
Exposure(s)
Genetic risk for schizophrenia (based on molecular genetics or family history).
This is defined as a person having a high number of risk alleles for schizophrenia, having copy number variants associated with schizophrenia, or having one or more first degree relatives with schizophrenia.
Comparator(s)/control(s)
Participants not at high genetic risk for schizophrenia based on either molecular genetics or family history
Context
Any setting.
Primary outcome(s)
Performance on tasks that test for cognitive biases associated with psychotic symptoms. Cognitive biases and perceptual biases that are associated with psychosis are those that have been reported as supporting the development and maintenance of psychosis.
This is defined as the following in these tasks:
The jumping-to-conclusions bias: This should either be the beads task or a conceptual equivalent.
Externalizing bias: A task that tests for a bias for misattributing internal thoughts or spoken words to an external source
Top-down processing: A task that tests for a top-down processing bias associated with hallucinations
External attribution bias: A task that tests for participants’ bias to attribute negative events to external sources
Belief inflexibility Bias: A task that tests for a bias against disconfirmatory evidence
Emotion recognition: Tasks that assess for affect perception deficits or facial emotion recognition task, such as the Penn Emotion Recognition Task.
Tasks that explicitly state that the outcome is a perceptual or cognitive bias associated with psychosis that is not one of the above mentioned tasks will be identified and included.
3
Secondary outcome(s)
None.
Data extraction (selection and coding)
Titles and abstracts of studies retrieved using the search strategy and those from additional sources will be screened to identify studies that potentially meet the inclusion criteria outlined above. The full texts of these potentially eligible studies will then be retrieved and independently assessed for eligibility by two review team members. Any disagreements between them over the eligibility of particular studies will be resolved through discussion with a third reviewer.
Risk of bias (quality) assessment
The quality of individual studies will be assessed by two independent reviewers using an assessment checklist which the reviewing team have developed based on the Newcastle-Ottawa Quality Assessment. Any discrepancies will be resolved by discussion with a third reviewer. The quality assessment for each study will inform the decision of whether to include the studies in data analysis and will add to the discussion of the quality of data available and therefore the potential areas for further research.
Strategy for data synthesis
We will provide a narrative synthesis of the findings from the included studies, or a meta-analysis if data allows.
4
Quality Assessment Tool (based on Newcastle-Ottawa Quality Assessment)
1) Selection of Participants
a) Reported as randomly or consecutively sampled (1 point)
b) No description or not random or consecutively sampled
2) Selection of recruited participants
a) Response rate reported (1 point)
c) No reported response rate
3) Comparability
a) The study controls for any potential confounding factors (1 points)
c) did not address any possible confounding factors
4) Selection of the low genetic risk group
a) Drawn from the same community and representative of the exposed cohort (1 point)
b) Drawn from a different source
c) No description of the derivation of the non-exposed cohort
Screening checklist
5
Is the paper published in a peer-reviewed journal?
Y/N
Does the paper include people at high risk for developing schizophrenia based on family history or genetics?
High risk based on family history should refer to first degree relatives with schizophrenia.
Y/N
Does the study measure a cognitive bias listed in the protocol or specifically state that it measures a cognitive bias associated with psychosis?
Y/N
Does the study compare participants that are or are not at high risk for developing schizophrenia, based on genetics or family history, on a cognitive bias task?
Y/N
6
Data collection template
Author_Year
Cognitive Bias
Country
Setting
Design
Criteria used to define high risk group
Sampling strategy
Response rate (if stated)
High risk (HR): n, mean age, %male, mean, SD
Low risk (control): n, mean age, %male, mean, SD
Cognitive bias test used
Comments on results
Confounders adjusted for
7
Prisma checklist
Section/topic # Checklist item Reported on page #
TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 1ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria,
participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
1
INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 1
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
1
METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide
registration information including registration number. 2
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.
2
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
2
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
Sup. 2
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
2
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
3
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
Supp. 6
Section/topic # Checklist item Reported on page #
8
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
3
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
4
RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for
exclusions at each stage, ideally with a flow diagram. Figure 1
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
Tables 1
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Table 1Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each
intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 5 – 6 (Figure 2-10)
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 5 – 6, (Figure 2-10)
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 1Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item
16]). 2
DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance
to key groups (e.g., healthcare providers, users, and policy makers). 8 - 9
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
10
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.
10
FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for
the systematic review. 10
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097
9
Table S1: Quality assessment results
Study
Sam
plin
g st
rate
gyRe
spon
se
rate
Adju
sted
fo
r con
-Se
lect
ion
of c
ontro
l
Tota
l sco
re
Confounders adjusted
Albacete (Albacete et al., 2016) 0 0 0 0 0 None
Alfimova et al., 2013 (Alfimova et al., 2013) 0 0 1 0 1 Sex, age, education
(Allott et al., 2015) 0 0 1 1 2 Age, IQ, symptoms
Andersen (Andersen et al., 2016) et al., 2016 0 0 1 0 1 Age, sex
Andric (Andric et al., 2016)et al., 2016 0 0 1 0 1 Age, gender, IQ, general facial recognition
Ay (Ay et al., 2016) et al., 2016 0 0 0 0 0 None
Bediou (Bediou et al., 2007)et al., 2007 0 0 1 0 1 Depression, age, education
Bolte (Bolte and Poustka, 2003) and Poustka, 2003 1 1 1 0 3 Gender, age, IQ
Calkins (Calkins et al., 2010)et al., 2010 0 0 1 1 2 Sex, age
Cella (Cella et al., 2015) et al., 2015 0 0 1 0 1 Age, gender, education, IQ, cognitive function
Coleman (Coleman et al., 2017) et al., 2017 1 1 1 1 4 White western European ancestry
Davalos (Davalos et al., 2004) et al., 2004 0 0 0 0 0 None
de Achaval (de Achaval et al., 2010)et al., 2010 1 0 1 0 2 Age, cognitive performance, education
Erol (Erol et al., 2010) et al., 2010 0 0 0 0 0 None
Germine (Germine et al., 2016) et al., 2016 1 0 1 1 3 white non-Hispanic ancestry
Goghari (Goghari et al., 2011)et al., 2011 0 0 1 0 1 Age
Goghari (Goghari et al., 2017) et al., 2017 0 0 1 0 1 age, sex, education, handedness, vocabulary
score, matric reasoning scoreGoldschmidt (Goldschmidt et
al., 2014) et al., 2014 0 0 0 0 0 None
Horton (Horton et al., 2017)et al., 2017 0 0 1 0 1 Age
Huepe (Huepe et al., 2012)et al., 2012 0 0 0 0 0 None
Ibanez (Ibanez et al., 2012)et al., 2012 0 0 1 0 1 Age
Kee (Kee, 2004), 2004 0 0 0 0 0 None
Kohler (Kohler et al., 2014)et al., 2014 0 0 1 1 2 family clusters, age, sex and psych history
Lavoie (Lavoie et al., 2014)et al., 2014 0 0 1 0 1 IQ, non-social reasoning, age, gender, SES
Leppanen (Leppanen et al., 2008) et al., 2008 0 0 0 0 0 Gender
Li (Li et al., 2010) et al., 2010 0 0 0 0 0 None
Li (Li et al., 2012) et al., 2012 0 0 0 0 0 None
McCown (McCown et al., 1989) et al., 1989 0 0 0 1 1 Gender
10
Mendoza (Mendoza et al., 2011) et al., 2011 0 0 1 0 1 Age, gender, education
Ruocco (Ruocco et al., 2014) et al., 2014 0 0 1 0 1 Age, race and sex
Spilka (Spilka and Goghari, 2017) and Goghari, 2017 0 0 0 0 0 None
Toomey (Toomey et al., 1999) et al., 1999 0 0 0 0 0 None
Wolf (Wolf et al., 2011) et al., 2011 0 0 1 0 1 None
Yang (Yang et al., 2015) et al., 2015 0 0 1 0 1 None
Footnote: see Quality Assessment Tool for details on how points were awarded.
Split emotions results
Anger
Study Control High riskN1 M1 SD1 N2 M2 SD2
Allott 2015 30 66.7 26.3 27 70.4 23.3Andric 2016 51 78.83 17.59 55 73.77 16.86Goghari 2011 36 88 12 23 90 12Goghari 2017 21 80.4 11.5 25 76 13.1Huepe 2012 18 5.5 1.5 14 5.5 2.1Leppanen 2008 22 0.8 0.23 23 0.7 0.31Mendoza 2011 109 0.95 0.12 110 0.9 0.21Ruocco 2014 380 0 1 332 -0.3 0.06
Meta-analysis results
Pooled SMD = 0.271 (95% CI = 0.126 to 0.417) Heterogeneity chi-squared = 8.72 (d.f. = 7) p = 0.273 I-squared (variation in SMD attributable to heterogeneity) = 19.7% Estimate of between-study variance Tau-squared = 0.0085 Test of SMD=0 : z= 3.65 p = 0.000
11
Forest plot
Disgust recognition
Study Control High risk N Mean SD N Mean SD
Allott 2015 30 74.4 28.6 27 71.6 27.3Huepe 2012 18 4 1.9 14 3.7 1.9Mendoza 2011 109 0.95 0.07 110 0.88 0.17
Meta-analysis results
SMD = 0.365 (95% CI = 0.065 - 0.666) Heterogeneity chi-squared = 2.72 (d.f. = 2) p = 0.257 I-squared (variation in SMD attributable to heterogeneity) = 26.5% Estimate of between-study variance Tau-squared = 0.0211 Test of SMD=0 : z= 2.39 p = 0.017
12
Forest plot
NOTE: Weights are from random effects analysis
. (-2.32, 3.05)with estimated predictive interval
Overall (I-squared = 26.5%, p = 0.257)
Mendoza 2011
Study
Allott 2015
Huepe 2012
0.37 (0.07, 0.67)
0.54 (0.27, 0.81)
SMD (95% CI)
0.10 (-0.42, 0.62)
0.16 (-0.54, 0.86)
100.00
58.57
Weight
25.62
%
15.80
0.37 (0.07, 0.67)
0.54 (0.27, 0.81)
SMD (95% CI)
0.10 (-0.42, 0.62)
0.16 (-0.54, 0.86)
100.00
58.57
Weight
25.62
%
15.80
0-.857 0 .857
Fear recognition
Study Control High risk N Mean SD N Mean SD
Allott 2015 30 73.3 25.4 27 50.6 29.8Andric 2016 51 66.44 17.14 55 63.55 16.83Goghari 2011 36 86 11 23 91 11Goghari 2017 21 69.4 15.7 25 68.8 16.2Huepe 2012 18 4.3 2.2 14 3.5 1.8Li 2012 12 78.33 10.08 12 78.75 7.11Mendoza 2011 109 0.98 0.05 110 0.87 0.23Ruocco 2014 380 0 1 332 -0.06 0.06
Meta-analysis results
13
SMD 0.227 (95% CI -0.046 to 0.500) Heterogeneity chi-squared = 25.35 (d.f. = 7) p = 0.001 I-squared (variation in SMD attributable to heterogeneity) = 72.4% Estimate of between-study variance Tau-squared = 0.0955 Test of SMD=0 : z= 1.63 p = 0.103
Forest plot
Happy
Study Control High riskN Mean SD N Mean SD
Allott 2015 30 100 0 27 96.3 10.7Andric 2016 51 87.03 10.22 55 89.57 12.14Goghari 2011 36 93 9 23 95 9Goghari 2017 21 93.4 6.1 25 93.3 6.4
14
Huepe 2012 18 7.8 0.5 14 7.07 1.8Li 2012 12 88.75 11.89 12 95 9.77Leppanen 2008 22 0.84 0.26 23 0.91 0.08Mendoza 2011 109 0.99 0.02 110 0.97 0.11Ruocco 2014 380 0 1 332 -0.1 0.05
Meta-analysis results
SMD 0.015 (95% CI -0.178 to 0.208) Heterogeneity chi-squared = 12.56 (d.f. = 7) p = 0.084 I-squared (variation in SMD attributable to heterogeneity) = 44.3% Estimate of between-study variance Tau-squared = 0.0290 Test of SMD=0 : z= 0.15 p = 0.878
Forest plot
Neutral recognition
Study Control High risk 15
N Mean SD N Mean SDAllott 2015 30 88.9 18.2 27 88.9 22.6Andric 2016 51 80.66 16.29 55 80.82 17Ruocco 2014 380 0 1 332 -0.34 0.07
Meta-analysis
SMD 0.201 (95% CI -0.171 to 0.573) Heterogeneity chi-squared = 7.29 (d.f. = 2) p = 0.026 I-squared (variation in SMD attributable to heterogeneity) = 72.6% Estimate of between-study variance Tau-squared = 0.0763 Test of SMD=0 : z= 1.06 p = 0.290
Forest plot
16
Sad recognition
Study Control High risk N Mean SD N Mean SD
Allott 2015 30 78.9 23.9 27 66.7 32Goghari 2011 36 87 11 23 91 11Goghari 2017 21 88.1 11.6 25 90 8.2Huepe 2012 18 4.7 2.9 14 5 1.9Mendoza 2011 109 0.93 0.11 110 0.85 0.18Ruocco 2014 380 0 1 332 0 0.06
Meta-analysis results
SMD 0.090 (95% CI -0.204 to 0.385) Heterogeneity chi-squared = 17.67 (d.f. = 5) p = 0.003 I-squared (variation in SMD attributable to heterogeneity) = 71.7% Estimate of between-study variance Tau-squared = 0.0837 Test of SMD=0 : z= 0.60 p = 0.548
Forest plot
17
Surprise recognition
Study Control High risk N Mean SD N Mean SD
Allott 2015 30 82.2 25.9 27 85.2 19.2Huepe 2012 18 6.7 1.3 14 6.2 1.4Mendoza 2011 109 0.98 0.05 110 0.94 0.14
Meta-analysis results
SMD 0.241 (95% CI -0.080 to 0.562) Heterogeneity chi-squared = 2.99 (d.f. = 2) p = 0.224 I-squared (variation in SMD attributable to heterogeneity) = 33.1% Estimate of between-study variance Tau-squared = 0.0291 Test of SMD=0 : z= 1.47 p = 0.141
Forest plot
NOTE: Weights are from random effects analysis
. (-2.76, 3.25)with estimated predictive interval
Overall (I-squared = 33.1%, p = 0.224)
Allott 2015
Study
Mendoza 2011
Huepe 2012
0.24 (-0.08, 0.56)
-0.13 (-0.65, 0.39)
SMD (95% CI)
0.38 (0.11, 0.65)
0.37 (-0.33, 1.08)
100.00
26.90
Weight
56.18
16.92
%
0.24 (-0.08, 0.56)
-0.13 (-0.65, 0.39)
SMD (95% CI)
0.38 (0.11, 0.65)
0.37 (-0.33, 1.08)
100.00
26.90
Weight
56.18
16.92
%
0-1.08 0 1.08
18
Forrest plot for neutral valence meta-analysis
19
Table 3 – results from meta-regression
Variable Coefficient Confidence interval P value Residual I2 (%)Quality score 0.1664494 -0.0105193 to 0.3434182 0.064 39.02%
Time limited test 0.0849263 -0.1979217 to 0.3677743 0.539 47.47Validated test 0.039321 -0.2579279 to 0.3365698 0.786 49.24%
20