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We develop a new longitudinal count data regression model that accounts for zero-inflation and spatio-temporal correlation across responses. This project is motivated by an analysis of Iowa Fluoride Study (IFS) data, a longitudinal cohort study with data on caries (cavity) experience scores measured for each tooth across five time points. To that end, we use a hurdle model for zero-inflation with two parts: the presence model indicating whether a count is non-zero through logistic regression and the severity model that considers the non-zero counts through a shifted Negative Binomial distribution allowing overdispersion. To incorporate dependence across measurement occasion and teeth, these marginal models are embedded within a Gaussian copula that introduces spatio-temporal correlations. A distinct advantage of this formulation is that it allows us to determine covariate effects with population-level (marginal) interpretations in contrast to mixed model choices. Standard Bayesian sampling from such a model is infeasible, so we use approximate Bayesian computing for inference. This approach is applied to the IFS data to gain insight into the risk factors for dental caries and the correlation structure across teeth and time.

As single-cell gene expression data analysis continues to grow, the need for reliable clustering methods has become increasingly important. The prevalence of heuristic means for method choice could lead to inaccurate reports if comprehensive evaluation of the methods is omitted. Typical comparisons of methods fail to address the complexity presented by the data, transformations, or internal parameters. Previous work in the field of microarray data provided measures to evaluate the stability characteristic of clustering algorithms. Additional work on aggregation in the same era presented a way to compare multiple methodologies using several performance measures. In this paper, we provide adaptations to these measures and employ two aggregation schemes to create ranked lists of method and parameter choices for six unique datasets. Our findings demonstrate that an ensemble of validation measures, combined with ranking based on measures' dataset specific preferences, provides an objective way to select clustering methodologies, taking into account characteristic evaluation from each measure.

Case-I interval-censored (current status) data from multistate systems are often encountered in cancer and other epidemiological studies. In this article, we focus on the problem of estimating state entry distribution and occupation probabilities, contingent on a preceding state occupation. This endeavor is particularly complex owing to the inherent challenge of the unavailability of directly observed counts of individuals at risk of transitioning from a state, due to the cross-sectional nature of the data. We propose two nonparametric approaches, one using the fractional at-risk set approach recently adopted in the right-censoring framework and the other a new estimator based on the ratio of marginal state occupation probabilities. Both estimation approaches utilize innovative applications of concepts from the competing risks paradigm. The finite-sample behavior of the proposed estimators is studied via extensive simulation studies where we show that the estimators based on severely censored current status data have good performance when compared with those based on complete data. We demonstrate the application of the two methods to analyze data from patients diagnosed with breast cancer., Comment: 19 pages, 5 tables, 4 figures

A recent breakthrough in differential network (DN) analysis of microbiome data has been realized with the advent of next-generation sequencing technologies. The DN analysis disentangles the microbial co-abundance among taxa by comparing the network properties between two or more graphs under different biological conditions. However, the existing methods to the DN analysis for microbiome data do not adjust for other clinical differences between subjects. We propose a Statistical Approach via Pseudo-value Information and Estimation for Differential Network Analysis (SOHPIE-DNA) that incorporates additional covariates such as continuous age and categorical BMI. SOHPIE-DNA is a regression technique adopting jackknife pseudo-values that can be implemented readily for the analysis. We demonstrate through simulations that SOHPIE-DNA consistently reaches higher recall and F1-score, while maintaining similar precision and accuracy to existing methods (NetCoMi and MDiNE). Lastly, we apply SOHPIE-DNA on two real datasets from the American Gut Project and the Diet Exchange Study to showcase the utility. The analysis of the Diet Exchange Study is to showcase that SOHPIE-DNA can also be used to incorporate the temporal change of connectivity of taxa with the inclusion of additional covariates. As a result, our method has found taxa that are related to the prevention of intestinal inflammation and severity of fatigue in advanced metastatic cancer patients., Comment: 23 pages, 2 figures, 4 tables

The differential network (DN) analysis identifies changes in measures of association among genes under two or more experimental conditions. In this article, we introduce a Pseudo-value Regression Approach for Network Analysis (PRANA). This is a novel method of differential network analysis that also adjusts for additional clinical covariates. We start from mutual information (MI) criteria, followed by pseudo-value calculations, which are then entered into a robust regression model. This article assesses the model performances of PRANA in a multivariable setting, followed by a comparison to dnapath and DINGO in both univariable and multivariable settings through variety of simulations. Performance in terms of precision, recall, and F1 score of differentially connected (DC) genes is assessed. By and large, PRANA outperformed dnapath and DINGO, neither of which is equipped to adjust for available covariates such as patient-age. Lastly, we employ PRANA in a real data application from the Gene Expression Omnibus (GEO) database to identify DC genes that are associated with chronic obstructive pulmonary disease (COPD) to demonstrate its utility. To the best of our knowledge, this is the first attempt of utilizing a regression modeling for DN analysis by collective gene expression levels between two or more groups with the inclusion of additional clinical covariates. By and large, adjusting for available covariates improves accuracy of a DN analysis., Comment: 5 figures, 6 tables, Presented at the ISMB 2022 (NetBio COSI)

Multistate current status (CS) data presents a more severe form of censoring due to the single observation of study participants transitioning through a sequence of well-defined disease states at random inspection times. Moreover, these data may be clustered within specified groups, and informativeness of the cluster sizes may arise due to the existing latent relationship between the transition outcomes and the cluster sizes. Failure to adjust for this informativeness may lead to a biased inference. Motivated by a clinical study of periodontal disease (PD), we propose an extension of the pseudo-value approach to estimate covariate effects on the state occupation probabilities (SOP) for these clustered multistate CS data with informative cluster or intra-cluster group sizes. In our approach, the proposed pseudo-value technique initially computes marginal estimators of the SOP utilizing nonparametric regression. Next, the estimating equations based on the corresponding pseudo-values are reweighted by functions of the cluster sizes to adjust for informativeness. We perform a variety of simulation studies to study the properties of our pseudo-value regression based on the nonparametric marginal estimators under different scenarios of informativeness. For illustration, the method is applied to the motivating PD dataset, which encapsulates the complex data-generation mechanism., Comment: 36 pages, 3 figures, 5 tables

Informative cluster size (ICS) arises in situations with clustered data where a latent relationship exists between the number of participants in a cluster and the outcome measures. Although this phenomenon has been sporadically reported in statistical literature for nearly two decades now, further exploration is needed in certain statistical methodologies to avoid potentially misleading inferences. For inference about population quantities without covariates, inverse cluster size reweightings are often employed to adjust for ICS. Further, to study the effect of covariates on disease progression described by a multistate model, the pseudo-value regression technique has gained popularity in time-to-event data analysis. We seek to answer the question: "How to apply pseudo-value regression to clustered time-to-event data when cluster size is informative?" ICS adjustment by the reweighting method can be performed in two steps; estimation of marginal functions of the multistate model and fitting the estimating equations based on pseudo-value responses, leading to four possible strategies. We present theoretical arguments and thorough simulation experiments to ascertain the correct strategy for adjusting for ICS. A further extension of our methodology is implemented to include informativeness induced by the intra-cluster group size. We demonstrate the methods in two real-world applications: (i) to determine predictors of tooth survival in a periodontal study, and (ii) to identify indicators of ambulatory recovery in spinal cord injury patients who participated in locomotor-training rehabilitation., Comment: 22 pages, 4 figures, 4 tables

We propose a novel personalized concept for the optimal treatment selection for a situation where the response is a multivariate vector, that could contain right-censored variables such as survival time. The proposed method can be applied with any number of treatments and outcome variables, under a broad set of models. Following a working semiparametric Single Index Model that relates covariates and responses, we first define a patient-specific composite score, constructed from individual covariates. We then estimate conditional means of each response, given the patient score, correspond to each treatment, using a nonparametric smooth estimator. Next, a rank aggregation technique is applied to estimate an ordering of treatments based on ranked lists of treatment performance measures given by conditional means. We handle the right-censored data by incorporating the inverse probability of censoring weighting to the corresponding estimators. An empirical study illustrates the performance of the proposed method in finite sample problems. To show the applicability of the proposed procedure for real data, we also present a data analysis using HIV clinical trial data, that contained a right-censored survival event as one of the endpoints.

Scientific studies in the last two decades have established the central role of the microbiome in disease and health. Differential abundance analysis seeks to identify microbial taxa associated with sample groups defined by a factor such as disease subtype, geographical region, or environmental condition. The results, in turn, help clinical practitioners and researchers diagnose disease and develop treatments more effectively. However, microbiome data analysis is uniquely challenging due to high-dimensionality, sparsity, compositionally, and collinearity. There is a critical need for unified statistical approaches for differential analysis in the presence of covariates. We develop a zero-inflated Bayesian nonparametric (ZIBNP) methodology that meets these multipronged challenges. The proposed technique flexibly adapts to the unique data characteristics, casts the high proportion of zeros in a censoring framework, and mitigates high-dimensionality and collinearity by utilizing the dimension-reducing property of the semiparametric Chinese restaurant process. Additionally, the ZIBNP approach relates the microbiome sampling depths to inferential precision while accommodating the compositional nature of microbiome data. Through simulation studies and analyses of the CAnine Microbiome during Parasitism (CAMP) and Global Gut microbiome datasets, we demonstrate the accuracy of ZIBNP compared to established methods for differential abundance analysis in the presence of covariates.

In spite of recent contributions to the literature, informative cluster size settings are not well known and understood. In this paper, we give a formal definition of the problem and describe it from different viewpoints. Data generating mechanisms, parametric and nonparametric models are considered in light of examples. Our emphasis is on nonparametric and robust approaches to the inference on the marginal distribution. Descriptive statistics and parameters of interest are defined as functionals and they are accompanied with a generally applicable testing procedure. The theory is illustrated with an example on patients with incomplete spinal cord injuries., Comment: Author produced version. Published version available at: https://link.springer.com/article/10.1007/s00362-013-0504-3