Can we blame fitness for surprising therapy outcomes? Andr Altmann - PowerPoint PPT Presentation

Can we blame fitness for surprising therapy outcomes? André Altmann Department of Computational Biology and applied Algorithmics Max Planck Institute for Informatics D-66123 Saarbrücken Germany Arevir Meeting 2009, Bonn, 23-24.04.2009

Introduction Viral fitness Here: replication capacity w/o presence of drugs Measure number of newly assembled infectious particles within a fixed time 1 day 1 day Only Protease and RT were studied, not the complete virus Is viral fitness useful for predicting response to ART? Can surprising treatment outcomes be explained by fitness? Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Dataset To study effect of RC during ART First build a model that predicts RC from genotype on datasets comprising genotype-RC pairs Fitness (RC) 80.1% 110.5% 52.3% 78.0% For this study two datasets were available 1. Monogram (Mark R Segal et al. Stat. Appl. Genet. Mol. Biol. 2004) 2. Erlangen (Hauke Walter et al. ) 317 and 253 samples Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Prediction of RC from genotype Training of a support vector machine (SVM) for each dataset 1. Linear SVM for selecting important mutations 2. Polynomial SVM for modeling synergetic effects between mutations Estimation of model performance (spearman correlation) Leave-one-out cross-validation on training data Monogram model ( ρ =0.546) Erlangen model ( ρ =0.542) Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Prediction of RC from genotype Important mutations in the linear SVM model The two training sets are quite different e.g. Erlangen sequences are highly mutated in the protease Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Intermediate conclusions Replication Capacity was predictable from genotype at moderate rates Performance can surely be improved with more genotype- phenotype pairs The pRC models selected different important mutations Is the quality of the prediction sufficient for studying the effect of RC on treatment response? Study behavior of pRC 1. Correlation of pRC with drug resistance 2. Correlation of pRC with treatment experience 3. Change of pRC during treatment interruptions Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Validation of predicted RC Monogram ρ =-0.534 Correlation of pRC with drug resistance 2,913 sequences (RT and Pro) from Eu Resist Integrated Database Resistance against 17 antiretroviral drugs was computed with Erlangen ρ =-0.233 geno2pheno Continuous value of predicted Fold Change (FC) was discretized using clinical cutoffs of geno2pheno Resistance against drugs was added: cumulative resistance score (CRS) Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Validation of pRC Correlation of pRC with drug resistance Same dataset, but single drugs For the Erlangen model a clear separation of drug classes is visible Pro sequences of Erlangen data were highly mutated 61% > 0 mutations 25% > 4 mutations For Monogram: 28% and 3% ! (Robert W Shafer et al. AIDS Rev.2008) Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Validation of predicted RC Correlation of pRC with treatment experience CRS ρ = 0.560 5,475 Pro and RT sequences from 3,869 patients extracted from the Monogram ρ = -0.336 Eu Resist DB CRS and pRC computed for all samples Erlangen ρ = -0.231 Correlated to number of treatment changes before genotyping Patients with >19 treatment changes formed one group and naïve patients formed largest group Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Validation of predicted RC Development of pRC during Development of pRC during treatment interruptions treatment p<0.03 p<0.015 p<0.01 p=0.02 162 sequences from 57 patients undergoing a treatment interruption Sequences were obtained at end of treatment and at max. 4 time points during the break Difference in pRC between baseline and first (n=56) or last (n=30) measure during the break Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Intermediate conclusions II Pre-existing notions about RC were confirmed using pRC 1. Inverse relation with drug resistance 2. Relation to treatment experience 3. Increase of RC during treatment interruptions The models are not perfect but good enough Using pRC can we … 1. … improve prediction of response to ART? 2. … explain surprising treatment outcomes? Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Relevance of pRC for inferring response to ART Extraction of TCEs from the Eu Resist database Baseline genotype, VL, and CD4 within 90 days before treatment start Follow-up measures at different time points Correlation of treatment activity score (TAS; PSS) and pRC with measurements at different time points Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Relevance of pRC for inferring response to ART Predicting change in VL and CD4 Linear regression model was trained using 1. Predicted resistance to applied drugs 2. TAS 3. Drug combination 4. Drug combination and TAS Models were built with and without pRC as covariate Performance was computed by 5x 5-fold cross-validation Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Relevance of pRC for inferring response to ART Fitness in equally active regimens VL 180 VL 180 CD4 360 CD4 360 Erlangen Monogram Erlangen Monogram Erlangen Monogram Erlangen Monogram VL 180 VL 180 CD4 360 CD4 360 Erlangen Monogram Erlangen Monogram Erlangen Monogram Erlangen Monogram Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Relevance of pRC for inferring response to ART P-values for all combinations 360: 1.0 – 3.0 180: 2.0 – 2.5 0.05% Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Final conclusions pRC showed a slight positive correlation with baseline VL … and a slight negative correlation with baseline CD4 Inclusion of pRC improved performance only moderately No significant improvement over the best method Resistance against applied antiretroviral drugs was dominant information for inferring response to ART Predicted RC was not significantly higher in virological failures Predicted RC was slightly increased in some immunological failures Do not blame the fitness! Blame resistance! Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009

Acknowledgements Thomas Lengauer Eugen Schülter Joachim Büch Melanie Balduin Hendrik Weisser Saleta Sierra Aragon Rolf Kaiser Klaus Korn Hauke Walter Anders Sönnerborg Monika Tschochner Francesca Incardona Maurizio Zazzi Thanks to Mark Segal for providing the Monogram dataset! Altmann, André Can we blame fitness for surprising therapy outcomes? – Arevir 2009 – 24.04.2009