A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome

Abstract

Anticipation, manifested through decreasing age of onset or increased severity in successive generations, has been noted in several genetic diseases. Statistical methods for genetic anticipation range from a simple use of the paired t-test for age of onset restricted to affected parent-child pairs, to a recently proposed random effects model which includes extended pedigree data and unaffected family members [Larsen et al., 2009]. A naive use of the paired t-test is biased for the simple reason that age of onset has to be less than the age at ascertainment (interview) for both affected parent and child, and this right truncation effect is more pronounced in children than in parents. In this paper, we first review different statistical methods for testing genetic anticipation in affected parent-child pairs that address the issue of bias due to right truncation. Using affected parent-child pair data, we compare the paired t-test with the parametric conditional maximum likelihood approach of Huang and Vieland [1997] and the nonparametric approach of Rabinowitz and Yang [1999] in terms of Type I error and power under various simulation settings and departures from the modeling assumptions. We especially investigate the issue of multiplex ascertainment and its effect on the different methods. We then focus on exploring genetic anticipation in Lynch syndrome and analyze new data on age of onset in affected parent-child pairs from families seen at the University of Michigan Cancer Genetics clinic with a mutation in one of the three main mismatch repair (MMR) genes. In contrast to the clinic-based population, we re-analyze data on a population-based Lynch syndrome cohort, derived from the Danish HNPCC-register. Both datasets indicate evidence of genetic anticipation in Lynch syndrome. We then expand our review to incorporate recently proposed statistical methods that consider family instead of affected pairs as the sampling unit. These prospective censored regression models offer additional flexibility to incorporate unaffected family members, familial correlation and other covariates into the analysis. An expanded dataset from the Danish HNPCC-register is analyzed by these alternative set of methods.

Telomere Shortening Is Associated with Genetic Anticipation in Chinese Von Hippel–Lindau Disease Families

“…Statisticians have been trying to design better methods to make anticipation test more accurate (30)(31)(32). Currently, there are two recommended methods, HV and RY2 tests, for anticipation analysis as they display a balance between reducing truncation bias and increasing examination efficiency (27). In this study, we used paired t test as well as HV and RY2 tests to treat our data and obtained identical results with statistical significance from the three methods (Table 2).…”

“…HV (parametric conditional maximum likelihood approach of Huang and Vieland) and RY2 (special nonparametric method of Rabinowitz and Yang) tests were used to lower the truncation bias when paired t test is conducted (27). t test was used to evaluate the difference of relative telomere length between patients with VHL disease and healthy controls, and paired t test to analyze the differences of age-adjusted relative telomere length in parent-child pairs.…”

Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension

“…Genetic anticipation is being sought in multiple diseases in which family clusters suggest a genetic link (11,12,(15)(16)(17)(18)22). Recent analysis of Crohn registries has used methods similar to our new approach to HPAH, and the results cast doubt on the phenomenon of genetic anticipation in most diseases without trinucleotide repeat expansions (11).…”

“…However, discovery of the meiotic expansion of repeating segments of trinucleotides and other DNA expansions as the basis for genetic anticipation in multiple neurological diseases, including Huntington disease, fragile X syndrome, and spinocerebellar ataxia, has led to reconsideration of the possibility of genetic anticipation in other diseases with familial clustering (13,14). These diseases of interest include Crohn disease, rheumatoid arthritis, psychiatric disorders, and HPAH (15)(16)(17)(18). Given that about 80% of heritable PAH is associated with mutations in the gene BMPR2, we previously considered the possibility of trinucleotide repeats in BMPR2 in our affected families.…”

Parental history of lupus and rheumatoid arthritis and risk in offspring in a nationwide cohort study: does sex matter?

“…As a simple comparison of age of onset distributions from each generation is inappropriate due to statistical considerations such as right truncation,45 various methods have been developed for the study of genetic anticipation, including newer methods that incorporate data from unaffected family members 46–50. Another direction will be to investigate familial autoimmunity in broader terms, rather than focusing on the patterns of single diseases within families.…”