Relating Genotype to Phenotype: Resampling-based Multiple Hypothesis Testing Using Order Statistics

• Activity Number: 98
• Type: Contributed
• Date/Time: Monday, August 8, 2005 : 8:30 AM to 10:20 AM
• Sponsor: Biometrics Section
• Author(s): Jennifer Schumi*+ and Victor DeGruttola
• Companies: Harvard School of Public Health and Harvard School of Public Health
• Keywords: Multiple hypothesis testing ; family-wise error rate ; genotype sequence ; phenotype ; resampling ; order statistics

Abstract

Development and spread of resistance to antiretroviral drugs limits their utility. We present multiple testing methods relating HIV genotype to phenotype. A semiparametric resampling approach identifies patterns of mutations at a set of relevant codons associated with changes in drug susceptibility with respect to wild-type. It compares observed, ordered, mean responses to expected order statistics from an unspecified error distribution, preserves the family-wise error rate asymptotically, and is approximately conservative in finite samples. Two applications use protease sequences and measures of in-vitro sensitivity from the Stanford HIV Drug Resistance Database. The first identifies patterns of mutations that enhance or decrease drug susceptibility; the second investigates interactions. This latter shows that while M46I/L mutations are associated with drug resistance, adding N88D/S mutations leads to hypersusceptible virus. Further addition of L90M mutations results in highly resistant virus. This allows the investigation of how mutations act in the presence of others and may suggest mechanisms by which resistance occurs or is reversed through the accumulation of mutations.