Methods for Long-Term Follow-Up of HIV-Infected Patients

描述(由申请人提供)：本申请描述了对基线或时变协变量(低维和高维)对重要生物标志物结果的重复测量的影响进行建模的参数和非参数方法。我们的第一个目标是考虑用参数方法来模拟病毒学或免疫学对治疗的反应。要有用，这种模型必须足够灵活，以允许标志物轨迹的突然和渐进变化，还必须纳入诸如耐药突变积累、宿主反应、治疗变化和联合感染后果等因素的影响。这些模型还必须考虑到事件性质和时间上的不确定性，比如导致这种变化的突变的发展，以及经常丢失的数据。大量可能的突变和这些突变之间的相互作用，以及多个病毒分支的存在，大量可能的治疗方法，以及治疗反应的多样性被测量，使得对耐药性的影响的建模具有挑战性。像CART这样的非参数方法可用来帮助降低遗传数据的维度，因此建议将变量包括在参数模型中，如上文所述。我们建议扩展CART方法以允许随时间重复的基因序列和病毒载量测量，并同时考虑参数和非参数纵向模型。我们的第二个目标是考虑一种基于重采样的方法来分析基线基因序列的影响，该方法是完全非参数的，并且允许任意测量次数。第三个目的是使用基于重新抽样的方法来测试最佳树中随时间的变化(使用重复序列)是否与耐药突变和治疗结果之间的恒定潜在关系一致，或者相反，暗示关系随着时间的推移而变化。我们的最终目标是开发非参数方法，用于将高维预测因子，如HIV基因或宿主基因SNPs，与感兴趣的反应之间的相关性，可能与其他协变量的调整联系起来。其目标是确定治疗反应中标志物之间不一致的预测因素。公共卫生相关性：该应用程序描述了参数和非参数方法，以描述基线或时变协变量(低维和高维)对重要结果的重复测量的影响，如病毒载量或免疫功能测量。挑战来自于这样一个事实，即在纵向生物标记物过程中可能会发生突变，这是因为耐药突变的发生等事件的确切时间无法观察到，以及病毒基因的高维性和不同类型审查的存在。我们建议的方法既包括适应病毒反弹或突变发展的不确定时间的高度灵活的纵向模型，也包括适应基因和病毒载量的重复测量的非参数探索性方法；后者不仅允许调查耐药突变模式和治疗反应之间的关系，而且还允许研究这种关系随时间的演变。

DESCRIPTION (provided by applicant): The application describes both parametric and non-parametric approaches to modeling the impact of baseline or time-varying covariates (both low- and high-dimensional) on repeated measures of important biomarker outcomes. Our first aim considers parametric approaches to modeling virological or immunological response to treatment. To be useful, such models must be flexible enough to allow abrupt as well as gradual changes in marker trajectories, and must also incorporate of the impact of factors such as accumulation of resistance mutations, host responses, treatment changes and consequences of co-infections. The models must also accommodate uncertainty in the nature and timing of events, like development of mutations, which cause such changes, as well as frequently missing data. Modeling the effect of resistance is made challenging by the large number of possible mutations and interactions among these mutations, as well as by the presence of multiple clades of virus, large numbers of possible treatments, and the variety of treatment response is measured. Non-parametric methods like CART are available to help reduce the dimensionality of genetic data, and therefore suggest variables for inclusion in parametric models, like those described above. We propose extending CART methodology to allow for both genetic sequences and viral load measurements that are repeated over time, and consider both parametric and non-parametric longitudinal models. Our second aim considers a resampling- based approach to analyze the effect of baseline genetic sequences that is fully nonparametric and allows arbitrary times of measurement. The third aim uses resampling-based methods to test whether variations in the best tree over time are (using the repeated sequences) are consistent with constant underlying relationships between resistance mutations and treatment outcomes, or instead imply that relationships change over time. Our final aim develops non-parametric methods for relating high-dimensional predictors, like HIV genotype or host genetic SNPs, to correlations between responses of interest, possibly with adjustment for other covariates. The goal is to identify predictors of discordance among markers in response to treatment. PUBLIC HEALTH RELEVANCE: The application describes both parametric and non-parametric approaches to describing the impact of baseline or time-varying covariates (both low- and high-dimensional) on repeated measures of important outcomes like viral load or measures of immune function. Challenges arise from the fact that abrupt changes can occur in longitudinal biomarker processes from events like development of resistance mutations whose exact timing is unobservable, as well as from the high dimensionality of the viral genotype and the presence of different types of censoring. Our proposed methods include both highly flexible longitudinal models that accommodate uncertain timing of viral rebound or development of mutations, and non-parametric exploratory methods that accommodate repeated measures of both genotype and viral load; not only does the latter permit investigation of the relationship between patterns of resistance mutations and responses to treatment, but also of the evolution of that relationship over time.