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Multiple Testing and Data Adaptive Regression: An Application to HIV-1 Sequence Data

Author

Listed:
  • Merrill Birkner

    (Division of Biostatistics, School of Public Health, University of California, Berkeley)

  • Sandra Sinisi

    (Division of Biostatistics, School of Public Health, University of California, Berkeley)

  • Mark van der Laan

    (Division of Biostatistics, School of Public Health, University of California, Berkeley)

Abstract

Analysis of viral strand sequence data and viral replication capacity could potentially lead to biological insights regarding the replication ability of HIV-1. Determining specific target codons on the viral strand will facilitate the manufacturing of target specific antiretrovirals. Various algorithmic and analysis techniques can be applied to this application. We propose using multiple testing to find codons which have significant univariate associations with replication capacity of the virus. We also propose using a data adaptive multiple regression algorithm to obtain multiple predictions of viral replication capacity based on an entire mutant/non-mutant sequence profile. The data set to which these techniques were applied consists of 317 patients, each with 282 sequenced protease and reverse transcriptase codons. Initially, the multiple testing procedure (Pollard and van der Laan, 2003) was applied to the individual specific viral sequence data. A single-step multiple testing procedure method was used to control the family wise error rate (FWER) at the five percent alpha level. Additional augmentation multiple testing procedures were applied to control the generalized family wise error (gFWER) or the tail probability of the proportion of false positives (TPPFP). Finally, the loss-based, cross-validated Deletion/Substitution/Addition regression algorithm (Sinisi and van der Laan, 2004) was applied to the dataset separately. This algorithm builds candidate estimators in the prediction of a univariate outcome by minimizing an empirical risk, and it uses cross-validation to select fine-tuning parameters such as: size of the regression model, maximum allowed order of interaction of terms in the regression model, and the dimension of the vector of covariates. This algorithm also is used to measure variable importance of the codons. Findings from these multiple analyses are consistent with biological findings and could possibly lead to further biological knowledge regarding HIV-1 viral data.

Suggested Citation

  • Merrill Birkner & Sandra Sinisi & Mark van der Laan, 2004. "Multiple Testing and Data Adaptive Regression: An Application to HIV-1 Sequence Data," U.C. Berkeley Division of Biostatistics Working Paper Series 1161, Berkeley Electronic Press.
    • Handle: RePEc:bep:ucbbio:1161
    Note: oai:bepress.com:ucbbiostat-1161
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    References listed on IDEAS

    as
    1. Dudoit Sandrine & van der Laan Mark J. & Pollard Katherine S., 2004. "Multiple Testing. Part I. Single-Step Procedures for Control of General Type I Error Rates," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 3(1), pages 1-71, June.
    2. van der Laan Mark J. & Dudoit Sandrine & Pollard Katherine S., 2004. "Augmentation Procedures for Control of the Generalized Family-Wise Error Rate and Tail Probabilities for the Proportion of False Positives," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 3(1), pages 1-27, June.
    3. Mark van der Laan & Sandrine Dudoit & Katherine Pollard, 2004. "Multiple Testing. Part III. Procedures for Control of the Generalized Family-Wise Error Rate and Proportion of False Positives," U.C. Berkeley Division of Biostatistics Working Paper Series 1140, Berkeley Electronic Press.
    4. Sandrine Dudoit & Mark van der Laan & Katherine Pollard, 2004. "Multiple Testing. Part I. Single-Step Procedures for Control of General Type I Error Rates," U.C. Berkeley Division of Biostatistics Working Paper Series 1137, Berkeley Electronic Press.
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