Human Heredity
Original Paper
Approaches to Familial Aggregation: Hypothesis Testing and Estimation when Families Are Selected through Parent Probands under a Variant of Single AscertainmentWickramaratne P.J.Department of Biostatistics, Joseph L. Mailman School of Public Health, and Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and Division of Clinical and Genetic Epidemiology, New York State Psychiatric Institute, New York, N.Y., USA
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Article / Publication Details
Received: December 18, 2003
Accepted: May 11, 2004
Published online: November 26, 2004
Issue release date: November 2004
Number of Print Pages: 12
Number of Figures: 0
Number of Tables: 1
ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)
For additional information: https://www.karger.com/HHE
Abstract
Epidemiologic approaches to testing and estimating familial aggregation of a disease consist of comparing rates of disease in relatives of individuals with the disease (known as case probands) with rates of disease in relatives of individuals without the disease (known as control probands). Gold et al. (J Am Stat Ass 1967;62: 409–420) derived an explicit mathematical model and sampling methods, under which this approach is equivalent to testing the null hypotheses that the disease risk in families is homogenous. A basic assumption of this model is that every family member has the same risk of disease and that disease status is independent among family members, although the disease risk may vary between families. When the disease is suspected of having a genetic component, rather than being purely environmental, this model has been shown to be appropriate for detecting disease aggregation in siblings, when relatives are siblings of probands. This model however is unrealistic for use in nuclear families when the affected status of offspring is not independent of the affected status of parents, and these families are selected through an affected or an unaffected parent, so that a parent is the proband and relatives are offspring of probands. We extend the Gold et al. model to allow for the disease risk in offspring to vary with the affected status of the parent. We assume that families are selected through affected and unaffected parents, under a variation of single ascertainment. Under this study design, we show that the usual test of association between affected status of probands and relatives, performed by comparing sample proportions of affected relatives of affected and unaffected probands, respectively, is no longer equivalent to a test of homogeneity of disease risk in offspring. Instead, it is equivalent to testing that the disease risk in offspring is independent of the number of affected parents. This test reduces to a test of homogeneity if and only if one assumes that the variation in disease risk in offspring, between families, is solely due to the variation in the number of affected parents. As a result, we show that under this study design, the standard χ2 test must be modified in order to obtain a valid test of familial aggregation. In addition the sample proportions of affected relatives of case and control probands, respectively, are shown to provide unbiased estimates of the expected risk of disease in an offspring given an affected/unaffected parent. We apply these results to methods of sample selection and discuss the practical implications of these findings.
© 2004 S. Karger AG, Basel
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References
-
Agresti A: Categorical Data Analysis. John Wiley & Sons, New York, 1990.
-
Berger A: On using index cases in the study of late-onset diseases. Stat Probabil Letters 1999;41:31–37.
External Resources
-
Gold R, Berman M, Berger A: On the question of whether a disease is familial. J Am Stat Assoc 1967;62:409–420.
External Resources
- Guo S: Inflation of sibling recurrence-risk ratio, due to ascertainment bias and/or overreporting. Am J Hum Genet 1998;63:252–258.
- Hunt SC, Hasstedt SJ, William RR: Testing for familial aggregation of a dichotomous trait. Genet Epidemiol 1986;3:299–312.
- Hodge SE, Vieland VJ: The essence of single ascertainment. Genetics 1996;144:1215–1223.
-
Khoury MJ, Beaty TH, Cohen BH: Fundamentals of Genetic Epidemiology. Oxford, Oxford University Press, 1993.
- Klein DN, Lewinsohn MP, Seeley JR, Rohde P: A family study of major depressive disorder in a community sample of adolescents. Arch Gen Psychiatry 2000;58:13–22.
-
Laird NM, Fitzmaurice GM, Schwartz AG: The analysis of case-control data: Epidemiologic studies of familial aggregation; in Sen PK, Rao CR (eds): Handbook of Statistics. Elsevier Science B.V. 2000, Vol 18, pp 465–482.
- Liang KY, Beaty TH: Measuring familial aggregation by using odds-ratio regression models. Genet Epidemiol 1991;8:361–370.
- Morton NE: Genetic tests under incomplete ascertainment. Am J Hum Genet 1959;11:1–16.
- Olsen JM, Cordell, JH: Ascertainment bias in the estimation of sibling genetic risk parameters. Genet Epidemiol 2000;18:217–235.
-
Sham P: Statistics in Human Genetics. London, Arnold, 1998.
- Stene J: Assumptions for different ascertainment models in human genetics. Biometrics 1977;33:523–527.
- Susser E, Susser M: Familial aggregation studies: A note on their epidemiologic properties. Am J Epidemiol 1989;129:23–30.
- Wickramaratne PJ, Greenwald S, Weissman MM: Psychiatric disorders in the relatives of probands with prepubertal-onset or adolescent- onset major depression. J Am Acad Child Adolesc Psychiatry 2000;39(11):1396–1405.
- Yu C, Zelterman Z: Statistical Inference for familial disease clustering. Biometrics 2002;58:481–491.
Article / Publication Details
Received: December 18, 2003
Accepted: May 11, 2004
Published online: November 26, 2004
Issue release date: November 2004
Number of Print Pages: 12
Number of Figures: 0
Number of Tables: 1
ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)
For additional information: https://www.karger.com/HHE
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