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Testing and developing statistical models for adoption studies of genetic and environmental influences of premature death

• Introduction and summary• Paper I: Case-control study of genetic and

environmental influences on premature death of adult adoptees. Genetic Epidemiology

• Paper II: Comparison of case-cohort estimators based on data on premature death of adult adoptees. Statistics in Medicine

• Paper III: Premature death of adult adoptees, analyses of a case-cohort sample. To appear in Genetic Epidemiology

• Paper IV: Inference methods for correlated left truncated lifetimes: parent and offspring relations in an adoption study. Submitted

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Main aims:

• Epidemiological: Quantify genetic and environmental effects on premature overall and cause-specific death among adult Danish adoptees

• Statistical: Investigate and compare different study designs and statistical methods that may be used in such adoption studies

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Data from Danish adoption register

• All 14 425 non-familial adoptions 1924-47

• Pedigree established and mortality traced through a number of different registers. Quite time consuming and costly for the early years.

• Different periods of follow-up in the four papers (paper I: July 8th 1982; papers II and III: April 1st 1993; paper IV: December 31st 1998)

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Aim at studying the dependence between life times of the adoptees and their four parents (biological and adoptive). Options:

• Consider simultaneously the life time of an adoptee and the life times of all its four parents

• Consider the life time of an adoptee and the life times of its two biological/adoptive parents (papers I-III)

• Consider the life times of an adoptee and the life time of each of its four types of parents (paper IV)

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Simultaneous or conditional modelling:

• Consider the joint distribution of the life time of an adoptee and the life time(s) of one or more of its parents (paper IV, one parent)

• Consider the conditional distribution of the life time of an adoptee given the life time(s) of one or more of its parents, or the other way around (papers I-III)

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Options for conditional modelling:

• Study the conditional distribution of life time of the adoptees by univariate survival analysis methods using dichotomized information on the life time of the parents (biological or adoptive) as covariates

• Study the conditional distribution of the lifetime of the parents (biological or adoptive) by univariate survival analysis methods using dichotomized information on the lifetime of the adoptee

• Study the conditional distribution of dichotomized life time of the adoptees by conditional logistic regression using dichotomized information on the lifetimes of the parents (biological or adoptive) as covariates

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Paper I:

Select case and control families according to whether adoptee was dead or alive 8 July 1982, matched by gender and date of birth of adoptee

Break the matching and analyse the data as a cohort of "case parents" and a cohort of "control parents" (biological or adoptive), concentrating on the age span 25-65 years

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Adopt a Cox model with separate baselines for mothers and fathers, and use a robust standard deviation to account for dependence between the life times of the parents

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A supplementary analysis use conditional logistic regression to analyze dichotomized life times of the adpotees with dichotomized life times of the parents as covariates

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Also a reanalysis of the cohort of adoptees born 1924-26 (as in Sørensen et al, 1988) with dichotomized life times of parents as covariates

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Paper I, p. 130:

Under which assumptions are the results comparable?

Could these have been investigated?

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Paper II:

Aim: Use simulations to study estimators for the regression coefficient and its variance for case-cohort data of the adoptees lifetimes using dichotomized information on parental life times as covariates

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Pseudo-likelihood for case-cohort:

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Results for estimation of the regression coefficient:

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Results for estimation of variances:

The bad results for the S&P variance estimator are surprising.

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Paper III:

Premature death of adult adoptees, analyses of a case-cohort sample

Liselotte Petersen. Per K. Andersen and Thorkild I. A. Sørensen

Aim: Analyse case-cohort data of the adoptees lifetimes using dichotomized information on parental life times as covariates using the methods studied in Paper II

Supplementary aim: Analyse the data as a cohort of "case parents" and a cohort of "control parents" (biological or adoptive) using dichotomized information on adoptees life times as covariates cf. paper I

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_

Case-cohort Cohorts of paren _ Total 1.27 (1.06 , 1.52) 1.16 (1.05 , 1.27)Natural 1.31 (1.04 , 1.63) 1.08 (0.96 , 1.23)Infections 1.67 (0.94 , 2.96) 1.10 (0.75 , 1.61)Respiratory 1.59 (0.61 , 4.00) 1.12 (0.59 , 2.10)Vascular 1.79 (1.20 , 2.68) 1.45 (1.14 , 1.84)Cancer 1.01 (0.69 , 1.48) 0.91 (0.70 , 1.20)

"Analysing parents' lifetimes, using adoptees' death as covariate gave the same overall picture, and, as expected, with more narrow confidence limits" (p. 78)

Results for biological parents (cf. tables 2 and 3):

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"The proportional hazards assumption was tested based on Schoenfeld's residuals [Schoenfled, 1982; Grambsch & Therneau, 1994] and could not be rejected" (p 77)

Are some modifications needed for case-cohort data?

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Paper IV:

Premature death of adult adoptees, analyses of a case-cohort sample

Liselotte Petersen. Per K. Andersen and Thorkild I. A. Sørensen

Aim: Analyse case-cohort data of the adoptees lifetimes using dichotomized information on parental life times as covariates using the methods studied in Paper II

Supplementary aim: Analyse the data as a cohort of "case parents" and a cohort of "control parents" (biological or adoptive) using dichotomized information on adoptees life times as covariates cf. paper I

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Dependence between life times

• Ta = life time of adoptee

• Tp = life time of one of the parents

• Main interest is in the dependence between Ta and Tp

• The study of this dependence is complicated by censoring and the available data

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