Recovering Information from Suppressed Plasma and CSF HIV Viral Load Using Multiple Imputation
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The document discusses the weekly presentations held by UC San Diego's Antiviral Research Center, focusing on current research and clinical practices related to various infectious diseases, particularly HIV. It highlights the importance of analyzing suppressed HIV viral loads and introduces statistical methods for handling censored data, essential for accurately assessing clinical outcomes. The presentation also covers findings from the Charter Study, which investigates the impact of HIV infection and treatments on neurocognitive functioning.
Recovering Information from Suppressed Plasma and CSF HIV Viral Load Using Multiple Imputation
- 1. AIDS CLINICAL ROUNDS The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
- 2. Recovering Information from Suppressed Plasma and CSF HIV Viral Load Florin Vaida, PhD Division of Biostatistics and Bioinformatics Department of Family and Preventive Medicine and HIV Neurobehavioral Research Center <fvaida@ucsd.edu> AIDS Clinical Rounds August 17, 2012 Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 1 / 23
- 3. HIV Viral Load HIV viral load is, together with CD4 T-cell count, the main marker of HIV disease In treated individuals HIV viral load is “suppressed” Suppressed VL = below the limit of detection of the assay 50 cp/ml for Roche Amplicor) HIV VL never goes as low as 0 The unknown (censored) VL in the 0-50 range contains important information for clinical research Importance for clinical practice? Dealing with censored VL requires more sophisticated statistical methods Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 2 / 23
- 4. CHARTER Study CNS HIV Antiretroviral Therapy Effects Research (CHARTER) project investigates effects of HIV infection and treatment on the brain Multicenter observational study, including San Diego site (HNRC) 1,500+ subjects 700+ subjects in longitudinal substudy, with 4,000+ visits HIV RNA measured in plasma and in 3,300 CSF samples Neurocognitive functioning measured at all visits Wide cross-sectional snapshot of HIV+ population, including treated and untreated individuals Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 3 / 23
- 5. Plasma HIV Viral Load in CHARTER 1316 subjects are either treatment naive or on HAART Plasma HIV VL (1296 samples) PLASMA Undetectable Detectable Total ART Naive 14 (5.5%) 237 (94%) 251 On HAART 576 (55%) 469 (45%) 1045 CSF HIV VL (1023 samples) CSF Undetectable Detectable Total ART Naive 51 (25%) 157 (75%) 208 On HAART 688 (84%) 127 (16%) 815 Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 4 / 23
- 6. Plasma HIV Viral Load, ART Naive Subjects ART Naive, Plasma ART Naive, Plasma 6 50 Plasma Log10 VL 5 Frequency 4 30 3 2 0 10 ? ? 1 1 2 3 4 5 6 7 -3 -2 -1 0 1 2 3 Plasma Log10 VL Normal Quantile Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 5 / 23
- 7. CSF HIV Viral Load, ART Naive Subjects ART Naive, CSF ART Naive, CSF 60 5 4 CSF Log10 VL Frequency 40 3 2 20 1 ? ? -1 0 0 -1 0 1 2 3 4 5 -3 -2 -1 0 1 2 3 CSF Log10 VL Normal Quantile Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 6 / 23
- 8. Plasma HIV Viral Load, Subjects On HAART Plasma VL, HAART Plasma VL, HAART 6 600 Plasma Log10 VL 4 Frequency 400 2 ? ? 0 200 -2 -4 0 -4 -2 0 2 4 6 -3 -2 -1 0 1 2 3 Plasma Log10 VL Normal Quantile Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 7 / 23
- 9. CSF HIV Viral Load, Subjects On HAART CSF VL, HAART CSF VL, HAART 600 4 CSF Log10 VL 2 Frequency ? 400 ? 0 -6 -4 -2 200 0 -6 -4 -2 0 2 4 -3 -2 -1 0 1 2 3 CSF Log10 VL Normal Quantile Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 8 / 23
- 10. How To Analyze Viral Load? VL (plasma and/or CSF) is a key outcome or predictor in HIV studies How to deal with VL in analyses? Option 1: VL detectable versus undetectable We throw away important information Not reasonable for ART naive subjects Option 2: Continuous VL (use 50 for undetectable subjects) May be OK when comparing two groups (e.g., treatment A vs. treatment B) Not OK in more complex analyses, e.g. controlling for baseline CD4 Awkward for subjects on ART Biased interpretation for means, differences b/w means Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 9 / 23
- 11. Statistical Methods for Censored Viral Load Option 3: Use more sophisticated statistical methods! Two main classes of statistical methods: 1 Methods for censored data 2 Imputation methods Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 10 / 23
- 12. Methods for Censored Viral Load Methods for censored data: usually treat VL as a censored response Methods are developed in the context of survival analysis E.g., if assuming that Log10 VL has a normal distribution, regression methods are equivalent to those for log-normal time-to-event Accelerated failure times (AFT) models Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 11 / 23
- 13. CSF VL as a function of CD4 cell counts, ART Naives ART naives: 25% undetectable in CSF Study association of CSF VL with CD4 Naive approach (use 50 cp/ml for undetectables): Regression equation: Log10 CSF VL = 3.506 - 0.00128 CD4 Moreover, non-linear association is suggested by plot 5.0 Log10 CSF VL 4.0 3.0 2.0 0 500 1000 1500 CD4 T-cell Count Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 12 / 23
- 14. CSF VL as a function of CD4 cell counts, ART Naives Log-normal AFT model, i.e. correct for censoring: Regression equation: Log10 CSF VL = 3.701 - 0.00198 CD4 5.0 Log10 CSF VL 4.0 3.0 2.0 0 500 1000 1500 CD4 T-cell Count 100 additional CD4 cells are associated with a CSF VL lower by 0.20 logs, not 0.12 logs Intuitively, the adjusted line is treating the censored CSF VL as if they were lower than 50 cp/ml Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 13 / 23
- 15. Multiple Imputation Impute (generate) censored CSF VL from the interval (0, 50) Multiple imputation accounts for uncertainty in censored values Best to impute using association with other variables, such as CD4 Usually assume normal distribution for log10 VL (fully observed) Distribution assumption more critical as proportion of censoring increases, e.g. for subjects on ART Alternative distributions are available, one can do a sensitivity analysis 5 4 Log10 CSF VL 3 2 x xxx x xx xxxxxx xx x xxx x x xxx x x x x x x xx x x x xx x x 1 0 500 1000 1500 CD4 T-cell Count Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 14 / 23
- 16. Viral Load in Longitudinal Studies VL collected over time is common in HIV studies Longitudinal studies present additional challenges: Modeling the time trajectory Dealing adequately with within-subject correlation Dealing with dropout Mixed-effects models and Generalized estimating equations (GEE) are powerful tools for longitudinal data Special methods are necessary to adjust for censored VL Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 15 / 23
- 17. Censored Viral Load in Longitudinal Studies One of my research interests: censored data in longitudinal studies (mixed effects models) Multiple imputation for MEM: Fitzgerald, Vaida, & DeGruttola (Stat in Medicine 2002) MEM with censored data: Vaida, Fitzgerald & DeGruttola (Comp Stat Data Analysis 2007) Vaida & Liu (J Comp Graph Stat 2009) lmec package in R (Vaida & Liu) 6 5 log10 HIV−1 RNA 4 3 N=71 58 57 43 34 24 13 2 0 3 6 9 12 15 18 21 24 Month of Treatment Interruption Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 16 / 23
- 18. Treatment Interruption of HIV (Saitoh et al., 2008) Unstructured Rx interruption in 72 adolescents, 4 sites in the US; observational study 50 40 30 CD4 % 20 10 0 0 3 6 9 12 15 18 21 24 Month of Treatment Interruption Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 17 / 23
- 19. Treatment Interruption of HIV (Saitoh et al., 2008) Observed mean CD4% seems to recover after 6 months 50 40 30 CD4 % 20 10 N=70 59 57 44 34 24 12 0 0 3 6 9 12 15 18 21 24 Month of Treatment Interruption Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 18 / 23
- 20. Treatment Interruption of HIV (Saitoh et al., 2008) CD4 % modeled via a mixed effects (random intercept) model: CD4%ij = µj + bi + eij Subject trajectories = parallel curves Model accounts for dropout (red), shows continuing CD4% decline: 50 40 30 CD4 % 20 10 N=70 59 57 44 34 24 12 0 0 3 6 9 12 15 18 21 24 Month of Treatment Interruption Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 19 / 23
- 21. Treatment Interruption of HIV (Saitoh et al., 2008): Plasma VL Mixed-effects (random intercept) profile model for log10 HIV VL, account for censoring (black line) 6 5 log10 HIV−1 RNA 4 3 N=71 58 57 43 34 24 13 2 0 3 6 9 12 15 18 21 24 Month of Treatment Interruption Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 20 / 23
- 22. Bi-exponential model for Viral Decay in ACTG315 (Vaida, Fitzgerald, & DeGruttola, 2007) Single-arm ART study (ZDV/3TC/RTV) in ART-naive patients Bi-exponential model for viral decay: VL(t) = A1 exp(−β1 t) + A2 exp(−β2 t) Use a mixed-effects model with random subject effects for β1 , β2 Account for censoring BLD Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 21 / 23
- 23. Bi-exponential model for Viral Decay in ACTG315 Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 22 / 23
- 24. Joint modeling of plasma and CSF VL in CHARTER MI using joint modeling of CSF and plasma VL Use correlation with CD4, duration of infection; ART naive subjects Ultimately, use imputed values to study association of VL with neurocognitive impairment R21 application submitted Florin Vaida (UCSD) Censored HIV Viral Load AIDS Clinical Rounds 23 / 23