Nested case-control sampling without replacement.

Nested case-control design (NCC) is a cost-effective outcome-dependent design in epidemiology that collects all cases and a fixed number of controls at the time of case diagnosis from a large cohort. Due to inefficiency relative to full cohort studies, previous research developed various estimation methodologies but changing designs in the formulation of risk sets was considered only in view of potential bias in the partial likelihood estimation. In this paper, we study a modified design that excludes previously selected controls from risk sets in view of efficiency improvement as well as bias. To this end, we extend the inverse probability weighting method of Samuelsen which was shown to outperform the partial likelihood estimator in the standard setting. We develop its asymptotic theory and a variance estimation of both regression coefficients and the cumulative baseline hazard function that takes account of the complex feature of the modified sampling design. In addition to good finite sample performance of variance estimation, simulation studies show that the modified design with the proposed estimator is more efficient than the standard design. Examples are provided using data from NIH-AARP Diet and Health Cohort Study.

Assessing risk model calibration with missing covariates.

When validating a risk model in an independent cohort, some predictors may be missing for some subjects. Missingness can be unplanned or by design, as in case-cohort or nested case-control studies, in which some covariates are measured only in subsampled subjects. Weighting methods and imputation are used to handle missing data. We propose methods to increase the efficiency of weighting to assess calibration of a risk model (i.e. bias in model predictions), which is quantified by the ratio of the number of observed events, $\mathcal{O}$, to expected events, $\mathcal{E}$, computed from the model. We adjust known inverse probability weights by incorporating auxiliary information available for all cohort members. We use survey calibration that requires the weighted sum of the auxiliary statistics in the complete data subset to equal their sum in the full cohort. We show that a pseudo-risk estimate that approximates the actual risk value but uses only variables available for the entire cohort is an excellent auxiliary statistic to estimate $\mathcal{E}$. We derive analytic variance formulas for $\mathcal{O}/\mathcal{E}$ with adjusted weights. In simulations, weight adjustment with pseudo-risk was much more efficient than inverse probability weighting and yielded consistent estimates even when the pseudo-risk was a poor approximation. Multiple imputation was often efficient but yielded biased estimates when the imputation model was misspecified. Using these methods, we assessed calibration of an absolute risk model for second primary thyroid cancer in an independent cohort.

Weight calibration to improve efficiency for estimating pure risks from the additive hazards model with the nested case-control design.

We study the efficiency of covariate-specific estimates of pure risk (one minus the survival function) when some covariates are only available for case-control samples nested in a cohort. We focus on the semiparametric additive hazards model in which the hazard function equals a baseline hazard plus a linear combination of covariates with either time-varying or time-invariant coefficients. A published approach uses the design-based inclusion probabilities to reweight the nested case-control data. We obtain more efficient estimates of pure risks by calibrating the design weights to data available in the entire cohort, for both time-varying and time-invariant covariate coefficients. We develop explicit variance formulas for the weight-calibrated estimates based on influence functions. Simulations show the improvement in precision by using weight calibration and confirm the consistency of variance estimators and the validity of inference based on asymptotic normality. Examples are provided using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study (PLCO).

Joint Estimation of Monotone Curves via Functional Principal Component Analysis.

A functional data approach is developed to jointly estimate a collection of monotone curves that are irregularly and possibly sparsely observed with noise. In this approach, the unconstrained relative curvature curves instead of the monotone-constrained functions are directly modeled. Functional principal components are used to describe the major modes of variations of curves and allow borrowing strength across curves for improved estimation. A two-step approach and an integrated approach are considered for model fitting. The simulation study shows that the integrated approach is more efficient than separate curve estimation and the two-step approach. The integrated approach also provides more interpretable principle component functions in an application of estimating weekly wind power curves of a wind turbine.

A binary hidden Markov model on spatial network for amyotrophic lateral sclerosis disease spreading pattern analysis.

Amyotrophic lateral sclerosis (ALS) is a neurological disease that starts at a focal point and gradually spreads to other parts of the nervous system. One of the main clinical symptoms of ALS is muscle weakness. To study spreading patterns of muscle weakness, we analyze spatiotemporal binary muscle strength data, which indicates whether observed muscle strengths are impaired or healthy. We propose a hidden Markov model-based approach that assumes the observed disease status depends on two latent disease states. The model enables us to estimate the incidence rate of ALS disease and the probability of disease state transition. Specifically, the latter is modeled by a logistic autoregression in that the spatial network of susceptible muscles follows a Markov process. The proposed model is flexible to allow both historical muscle conditions and their spatial relationships to be included in the analysis. To estimate the model parameters, we provide an iterative algorithm to maximize sparse-penalized likelihood with bias correction, and use the Viterbi algorithm to label hidden disease states. We apply the proposed approach to analyze the ALS patients' data from EMPOWER Study.

Weight calibration to improve the efficiency of pure risk estimates from case-control samples nested in a cohort.

Cohort studies provide information on relative hazards and pure risks of disease. For rare outcomes, large cohorts are needed to have sufficient numbers of events, making it costly to obtain covariate information on all cohort members. We focus on nested case-control designs that are used to estimate relative hazard in the Cox regression model. In 1997, Langholz and Borgan showed that pure risk can also be estimated from nested case-control data. However, these approaches do not take advantage of some covariates that may be available on all cohort members. Researchers have used weight calibration to increase the efficiency of relative hazard estimates from case-cohort studies and nested cased-control studies. Our objective is to extend weight calibration approaches to nested case-control designs to improve precision of estimates of relative hazards and pure risks. We show that calibrating sample weights additionally against follow-up times multiplied by relative hazards during the risk projection period improves estimates of pure risk. Efficiency improvements for relative hazards for variables that are available on the entire cohort also contribute to improved efficiency for pure risks. We develop explicit variance formulas for the weight-calibrated estimates. Simulations show how much precision is improved by calibration and confirm the validity of inference based on asymptotic normality. Examples are provided using data from the American Association of Retired Persons Diet and Health Cohort Study.

Autologistic network model on binary data for disease progression study.

This paper focuses on analysis of spatiotemporal binary data with absorbing states. The research was motivated by a clinical study on amyotrophic lateral sclerosis (ALS), a neurological disease marked by gradual loss of muscle strength over time in multiple body regions. We propose an autologistic regression model to capture complex spatial and temporal dependencies in muscle strength among different muscles. As it is not clear how the disease spreads from one muscle to another, it may not be reasonable to define a neighborhood structure based on spatial proximity. Relaxing the requirement for prespecification of spatial neighborhoods as in existing models, our method identifies an underlying network structure empirically to describe the pattern of spreading disease. The model also allows the network autoregressive effects to vary depending on the muscles' previous status. Based on the joint distribution derived from this autologistic model, the joint transition probabilities of responses among locations can be estimated and the disease status can be predicted in the next time interval. Model parameters are estimated through maximization of penalized pseudo-likelihood. Postmodel selection inference was conducted via a bias-correction method, for which the asymptotic distributions were derived. Simulation studies were conducted to evaluate the performance of the proposed method. The method was applied to the analysis of muscle strength loss from the ALS clinical study.

A Longitudinal Analysis of Respiratory Illness and Tobacco Use Transitions.

INTRODUCTION: Among individuals with chronic respiratory conditions, transitions between patterns of tobacco product use are not well understood. This study examines how transitions, including quitting altogether, differ over time between those who do and do not have chronic respiratory conditions. METHODS: Data from youth and adult participants of the longitudinal Population Assessment of Tobacco and Health Study (2013-2018) were analyzed. Youth aged 12-17 years were included if they had aged into the adult sample by Wave 4. Stratified polytomous regression models built under a first-order Markov assumption modeled the probability of transitioning between different states/patterns of tobacco product use (exclusive current E-cigarette use, exclusive current combustible tobacco product use, current dual use of combustible products and E-cigarettes, and no current tobacco product use) at each wave. Marginal transition probabilities were computed as a function of ever or past-year diagnosis of a respiratory condition (separately for asthma and a composite variable representing chronic bronchitis, emphysema, and/or chronic obstructive pulmonary disease). Analyses were conducted in 2020-2021. RESULTS: Most individuals, regardless of respiratory condition, maintained the same pattern of tobacco use between waves. Exclusive combustible tobacco product users, including those with or without a respiratory condition, were not likely to become exclusive E-cigarette users or to quit using tobacco entirely. CONCLUSIONS: Although combustible tobacco use negatively impacts the management and prognosis of respiratory illnesses, combustible tobacco users who were recently diagnosed with a chronic respiratory condition were not likely to quit using tobacco. Efforts to encourage and support cessation in this medically vulnerable population should be increased.