Geno2pheno: Estimating phenotypic drug resistance from HIV-1 genotypes

Abstract

Therapeutic success of anti-HIV therapies is limited by the development of drug resistant viruses. These genetic variants display complex mutational patterns in their pol gene, which codes for protease and reverse transcriptase, the molecular targets of current antiretroviral therapy. Genotypic resistance testing depends on the ability to interpret such sequence data, whereas phenotypic resistance testing directly measures relative in vitro susceptibility to a drug. From a set of 650 matched genotype-phenotype pairs we construct regression models for the prediction of phenotypic drug resistance from genotypes. Since the range of resistance factors varies considerably between different drugs, two scoring functions are derived from different sets of predicted phenotypes. Firstly, we compare predicted values to those of samples derived from 178 treatment-naive patients and report the relative deviance. Secondly, estimation of the probability density of 2000 predicted phenotypes gives rise to an intrinsic definition of a susceptible and a resistant subpopulation. Thus, for a predicted phenotype, we calculate the probability of membership in the resistant subpopulation. Both scores provide standardized measures of resistance that can be calculated from the genotype and are comparable between drugs. The geno2pheno system makes these genotype interpretations available via the Internet (http://www.genafor.org/).

Figure 1

Histogram data and fitted normal density for predicted resistance factors from subtype B genotypes derived from 124 treatment-naive patients. The bottom x-axes refer to log₁₀ resistance factors (RF), whereas the top x-axes denote z-scores (numbers of standard deviations from the mean).

Figure 2

Histogram data and Gaussian mixture model fit for predicted resistance factors for 2000 samples drawn randomly from the population. Displayed are the bimodal mixture density (black line) and the densities for the suscepatible (dashed green line) and resistant (dashed red line) subpopulations. The conditional class probability of belonging to the resistant subpopulation given the predicted phenotype is plotted as a blue line.

Figure 3

Screenshot showing part of the output of the geno2pheno web service. Three-letter drug codes are given in the caption of Table 1. The table contains classification results [columns three and four, discussed in (3,4)], predicted phenotypes (column five), z-scores (column six) and probability scores (column seven). Only classification results are affected by the choice of cut-offs.