Association Tests for Traits with Variable Age at Onset

Mokliatchouk, Oksana; Blacker, Deborah; Rabinowitz, Daniel

doi:10.1159/000022959

Cited by 20 publications

(19 citation statements)

References 28 publications

(27 reference statements)

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“…In the following we motivate this coding by showing that in this case, equation (1) takes on the same form as the score equation of a proportional hazards model with an exponential baseline hazard function (this approach can also be generalised to the Cox proportional hazards model. 11 Score equations should merely be considered a (valid) device for coming up with test statistics, see the Discussion.…”

Section: Simple Strategies For Data Analysismentioning

confidence: 99%

The family based association test method: strategies for studying general genotype–phenotype associations

2001

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With possibly incomplete nuclear families, the family based association test (FBAT) method allows one to evaluate any test statistic that can be expressed as the sum of products (covariance) between an arbitrary function of an offspring's genotype with an arbitrary function of the offspring's phenotype. We derive expressions needed to calculate the mean and variance of these test statistics under the null hypothesis of no linkage. To give some guidance on using the FBAT method, we present three simple data analysis strategies for different phenotypes: dichotomous (affection status), quantitative and censored (eg, the age of onset). We illustrate the approach by applying it to candidate gene data of the NIMH Alzheimer Disease Initiative. We show that the RC-TDT is equivalent to a special case of the FBAT method. This result allows us to generalise the RC-TDT to dominant, recessive and multi-allelic marker codings. Simulations compare the resulting FBAT tests to the RC-TDT and the S-TDT. The FBAT software is freely available. European Journal of Human Genetics (2001) 9, 301 ± 306.

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Section: Simple Strategies For Data Analysismentioning

confidence: 99%

The family based association test method: strategies for studying general genotype–phenotype associations

2001

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“…Li and Fan (2000) proposed a linkage disequilibrium-based Cox (LDCox) model for nuclear family data and used a robust Wald's test for association. Mokliatchouk et al (2001) and Shih and Whittemore (2002) developed likelihood-based score statistics to test for association between a disease and a genetic marker. The score statistic can be written as a weighted sum over family members of their observed minus expected genotypes.…”

Section: Survival Analysis Methods For Family-based Association Testsmentioning

confidence: 99%

Survival Analysis Methods in Genetic Epidemiology

Li¹

2007

Current Topics in Human Genetics

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Mapping genes for complex human diseases is a challenging problem due to the fact that many such diseases are due to both genetic and enviromental risk factors and many also exhibit phenotypic heterogeneity, such as variable age of onset. Information on variable age of disease onset is often a good indicator for disease heterogeneity and incorporation of such information together with enviromental risk factors into genetic analysis should lead to more powerful tests for genetic analysis. Due to the problem of censoring, survival analysis methods have proved to be very useful for genetic analysis. In this paper, I review some recent methodological developments on integrating modern survival analysis methods and human genetics in order to rigorously incorporate both age of onset and enviromental covariates data into aggregation analysis, segregation analysis, linkage analysis, association analysis and gene risk characterization. I also briefly discuss the issue of ascertainment correction and survival analysis methods for high-dimensional genomic data. Finally, I outline several areas that need further methodological developments. Survival Analysis Methods in Genetic Epidemiology AbstractMapping genes for complex human diseases is a challenging problem due to the fact that many such diseases are due to both genetic and environmental risk factors and many also exhibit phenotypic heterogeneity, such as variable age of onset. Information on variable age of disease onset is often a good indicator for disease heterogeneity and incorporation of such information together with environmental risk factors into genetic analysis should lead to more powerful tests for genetic analysis. Due to the problem of censoring, survival analysis methods have proved to be very useful for genetic analysis. In this paper, I review some recent methodological developments on integrating modern survival analysis methods and human genetics in order to rigorously incorporate both age of onset and environmental covariates data into aggregation analysis, segregation analysis, linkage analysis, association analysis and gene risk characterization. I also briefly discuss the issue of ascertainment correction and survival analysis methods for high-dimensional genomic data. Finally, I outline several areas that need further methodological developments.

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“…In this context the logrank test compares the rates with which individuals of different genotypes are diagnosed with ADHD. When the Breslow estimator is used, it can be shown that this methodology is equivalent to the proportional hazards approaches of Mokliatchouk et al (2001). When parental genotypes are known the FBAT-logrank is also equivalent to Shih & Whittemore's (2002) method.…”

Section: Family-based Association Test-logrank (Fbat-logrank)mentioning

confidence: 99%

Evidence for an Association of the Dopamine D5 Receptor Gene on Age at Onset of Attention Deficit Hyperactivity Disorder

Lasky‐Su

Biederman

Laird

et al. 2007

Annals of Human Genetics

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SummaryThe purpose of this study was to determine whether the single nucleotide polymorphisms (SNPs) within candidate genes for attention deficit hyperactivity disorder (ADHD) are associated with the age at onset for ADHD. One hundred and forty-three SNPs were genotyped across five candidate genes (DRD5, SLC6A3, HTR1B, SNAP25, DRD4) for ADHD in 229 families with at least one affected offspring. SNPs with the highest estimated power to detect an association with age at onset were selected for each candidate gene, using a power-based screening procedure that does not compromise the nominal significance level. A time-to-onset analysis for family-based samples was performed on these SNPs to determine if an association exists with age at onset for ADHD. Seven consecutive SNPs surrounding the D5 dopamine receptor gene (DRD5), were associated with the age at onset for ADHD; FDR adjusted q-values ranged from 0.008 to 0.023. This analysis indicates that individuals with the risk genotype develop ADHD earlier than individuals with any other genotype. A haplotype analysis across the 6 significant SNPs that were in linkage disequilibrium with one another, CTCATA, was also found to be significant (p-value = 0.02). We did not observe significant associations with age at onset for the other candidate loci tested. Although definitive conclusions await independent replication, these results suggest that a variant in DRD5 may affect age at onset for ADHD.

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Association Tests for Traits with Variable Age at Onset

Cited by 20 publications

References 28 publications

The family based association test method: strategies for studying general genotype–phenotype associations

The family based association test method: strategies for studying general genotype–phenotype associations

Survival Analysis Methods in Genetic Epidemiology

Evidence for an Association of the Dopamine D5 Receptor Gene on Age at Onset of Attention Deficit Hyperactivity Disorder

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