Estimating age-specific incidence of dementia using prevalent cohort data

In prospective cohort studies individuals are usually recruited according to a certain cross-sectional sampling criterion. The prevalent cohort is defined as a group of individuals who are alive but possibly with disease at the beginning of the study. It is appealing to incorporate the prevalent cases to estimate the incidence rate of disease before the enrollment. The method of back calculation of incidence rate has been used to estimate the incubation time from HIV infection to AIDS. The time origin is defined as the time of HIV infection. In aging cohort studies, the primary time scale is age of disease onset, subjects have to survive certain years to be enrolled into the study, thus creating left truncation (delay entry). The current methods usually assume that either the disease incidence is rare or the excess mortality due to disease is small compared to the healthy subjects. By far the validity of the results based on these assumptions has not been examined. In this paper, a simple alternative method is proposed to estimate dementia incidence rate before enrollment using prevalent cohort data with left truncation. Furthermore simulations are used to examine the performance of the estimation of disease incidence under different assumptions of disease incidence rates and excess mortality hazards due to disease. As application, the method is applied to the prevalent cases of dementia from the Honolulu Asia Aging Study to estimate dementia incidence rate and to assess the effect of hypertension, Apoe 4 and education on dementia onset.     

Estimating age-specific incidence of dementia using prevalent cohort data

In prospective cohort studies, individuals are usually recruited according to a certain cross-sectional sampling criterion. The prevalent cohort is defined as a group of individuals who are alive but possibly with disease at the beginning of the study. It is appealing to incorporate the prevalent cases to estimate the incidence rate of disease before the enrollment. The method of back calculation of incidence rate has been used to estimate the incubation time from human immunodeficiency virus (HIV) infection to AIDS. The time origin is defined as the time of HIV infection. In aging cohort studies, the primary time scale is age of disease onset, subjects have to survive certain years to be enrolled into the study, thus creating left truncation (delay entry). The current methods usually assume that either the disease incidence is rare or the excess mortality due to disease is small compared with the healthy subjects. So far the validity of the results based on these assumptions has not been examined. In this paper, a simple alternative method is proposed to estimate dementia incidence rate before enrollment using prevalent cohort data with left truncation. Furthermore, simulations are used to examine the performance of the estimation of disease incidence under different assumptions of disease incidence rates and excess mortality hazards due to disease. As application, the method is applied to the prevalent cases of dementia from the Honolulu-Asia Aging Study to estimate the dementia incidence rate and to assess the effect of hypertension, Apoe 4 and education on dementia onset.     

A Bayesian semiparametric method for analyzing length-biased data

Survival data obtained from prevalent cohort study designs are often subject to length-biased sampling. Frequentist methods including estimating equation approaches, as well as full likelihood methods, are available for assessing covariate effects on survival from such data. Bayesian methods allow a perspective of probability interpretation for the parameters of interest, and may easily provide the predictive distribution for future observations while incorporating weak prior knowledge on the baseline hazard function. There is lack of Bayesian methods for analyzing length-biased data. In this paper, we propose Bayesian methods for analyzing length-biased data under a proportional hazards model. The prior distribution for the cumulative hazard function is specified semiparametrically using I-Splines. Bayesian conditional and full likelihood approaches are developed for analyzing simulated and real data.     

Relative risk regression for current status data in case‐cohort studies

We propose using the weighted likelihood method to fit a general relative risk regression model for the current status data with missing data as arise, for example, in case‐cohort studies. The missingness probability is either known or can be reasonably estimated. Asymptotic properties of the weighted likelihood estimators are established. For the case of using estimated weights, we construct a general theorem that guarantees the asymptotic normality of the M‐estimator of a finite dimensional parameter in a class of semiparametric models, where the infinite dimensional parameter is allowed to converge at a slower than parametric rate, and some other parameters in the objective function are estimated a priori. The weighted bootstrap method is employed to estimate the variances. Simulations show that the proposed method works well for finite sample sizes. A motivating example of the case‐cohort study from an HIV vaccine trial is used to demonstrate the proposed method. The Canadian Journal of Statistics 39: 557–577; 2011. © 2011 Statistical Society of Canada     

A nonlinear mixed-effects model for multivariate longitudinal data with partially observed outcomes with application to HIV disease dynamics

The measurable multiple bio-markers for a disease are used as indicators for studying the response variable of interest in order to monitor and model disease progression. However, it is common for subjects to drop out of the studies prematurely resulting in unbalanced data and hence complicating the inferences involving such data. In this paper we consider a case where data are unbalanced among subjects and also within a subject because for some reason only a subset of the multiple outcomes of the response variable are observed at any one occasion. We propose a nonlinear mixed-effects model for the multivariate response variable data and derive a joint likelihood function that takes into account the partial dropout of the outcomes of the response variable. We further show how the methodology can be used in the estimation of the parameters that characterise HIV disease dynamics. An approximation technique of the parameters is also given and illustrated using a routine observational HIV dataset.     

Accounting for Follow-up Bias in Estimation of Human Immunodeficiency Virus Incidence Rates

The objective of this paper is to describe methods for estimating current incidence rates for human immunodeficiency virus (HIV) that account for follow-up bias. Follow-up bias arises when the incidence rate among individuals in a cohort who return for follow-up is different from the incidence rate among those who do not return. The methods are based on the use of early markers of HIV infection such as p24 antigen. The first method, called the cross-sectional method, uses only data collected at an initial base-line visit. The method does not require follow-up data but does require a priori knowledge of the mean duration of the marker (μ). A confidence interval procedure is developed that accounts for uncertainty in μ. The second method combines the base-line data from all individuals together with follow-up data from those individuals who return for follow-up. This method has the distinct advantage of not requiring prior information about μ. Several confidence interval procedures for the incidence rate are compared by simulation. The methods are applied to a study in India to estimate current HIV incidence. These data suggest that the epidemic is growing rapidly in some subpopulations in India.     

A formal test for the stationarity of the incidence rate using data from a prevalent cohort study with follow-up

In a prevalent cohort study with follow-up, the incidence process is not directly observed since only the onset times of prevalent cases can be ascertained. Assessing the “stationarity” of the underlying incidence process can be important for at least three reasons, including an improvement in efficiency when estimating the survivor function. We propose, for the first time, a formal test for stationarity using data from a prevalent cohort study with follow-up. The test makes use of a characterization of stationarity, an extension of this characterization developed in this paper, and of a test for matched pairs of right censored data. We report the results from a power study assuming varying degrees of departure from the null hypothesis of stationarity. The test is also applied to data obtained as part of the Canadian Study of Health and Aging (CSHA) to verify whether the incidence rate of dementia amongst the elderly in Canada has remained constant.     

Bivariate modelling of longitudinal measurements of two human immunodeficiency type 1 disease progression markers in the presence of informative drop-outs

Summary.  The main statistical problem in many epidemiological studies which involve repeated measurements of surrogate markers is the frequent occurrence of missing data. Standard likelihood-based approaches like the linear random-effects model fail to give unbiased estimates when data are non-ignorably missing. In human immunodeficiency virus (HIV) type 1 infection, two markers which have been widely used to track progression of the disease are CD4 cell counts and HIV–ribonucleic acid (RNA) viral load levels. Repeated measurements of these markers tend to be informatively censored, which is a special case of non-ignorable missingness. In such cases, we need to apply methods that jointly model the observed data and the missingness process. Despite their high correlation, longitudinal data of these markers have been analysed independently by using mainly random-effects models. Touloumi and co-workers have proposed a model termed the joint multivariate random-effects model which combines a linear random-effects model for the underlying pattern of the marker with a log-normal survival model for the drop-out process. We extend the joint multivariate random-effects model to model simultaneously the CD4 cell and viral load data while adjusting for informative drop-outs due to disease progression or death. Estimates of all the model's parameters are obtained by using the restricted iterative generalized least squares method or a modified version of it using the EM algorithm as a nested algorithm in the case of censored survival data taking also into account non-linearity in the HIV–RNA trend. The method proposed is evaluated and compared with simpler approaches in a simulation study. Finally the method is applied to a subset of the data from the 'Concerted action on seroconversion to AIDS and death in Europe' study.     

Maximum Likelihood Estimations and EM Algorithms with Length-biased Data

Length-biased sampling has been well recognized in economics, industrial reliability, etiology applications, epidemiological, genetic and cancer screening studies. Length-biased right-censored data have a unique data structure different from traditional survival data. The nonparametric and semiparametric estimations and inference methods for traditional survival data are not directly applicable for length-biased right-censored data. We propose new expectation-maximization algorithms for estimations based on full likelihoods involving infinite dimensional parameters under three settings for length-biased data: estimating nonparametric distribution function, estimating nonparametric hazard function under an increasing failure rate constraint, and jointly estimating baseline hazards function and the covariate coefficients under the Cox proportional hazards model. Extensive empirical simulation studies show that the maximum likelihood estimators perform well with moderate sample sizes and lead to more efficient estimators compared to the estimating equation approaches. The proposed estimates are also more robust to various right-censoring mechanisms. We prove the strong consistency properties of the estimators, and establish the asymptotic normality of the semi-parametric maximum likelihood estimators under the Cox model using modern empirical processes theory. We apply the proposed methods to a prevalent cohort medical study. Supplemental materials are available online.     

Data and projections of HIV/AIDS cases in Portugal: an unstoppable epidemic?

The size of the affected population with HIV/AIDS is a vital question asked by healthcare providers. A statistical procedure called Back-calculation has been the most widely used method to answer that question. Recent discussions suggest that this method is gradually becoming less appropriate for reliable incidence and prevalence estimates, as it does not take into account the effect of treatment. In spite of this, in the current paper that method and a worst-case scenario are used to assess the quality of previous projections and obtain new ones. The first problem faced was the need to account for reporting delays, no reporting and underreporting. The adjusted AIDS incidence data were then used to obtain lower bounds on the size of the AIDS epidemic, using the back-calculation methodology. A Weibull and Gamma distribution was considered for the latency period distribution. The EM algorithm was applied to obtain maximum likelihood estimates of the HIV incidence. The density of infection times was parameterized as a step function. The methodology is applied to AIDS incidence in Portugal for four different transmission categories (injecting drug users, heterosexual, homo/bisexual and other) to obtain short-term projections (2002–2005) and an estimate of the minimum size of the epidemic.     

A risk set adjustment for proportional hazards modeling of combined cohort data

Sporting careers observed over a preset time interval can be partitioned into two distinct subsamples. These samples consist of individuals whose careers had already commenced at the start of the time interval (prevalent subsample) and individuals whose careers began during the time interval (incident subsample) as well the respective individual-level covariate data such as salary, height, weight, performance statistics, draft position, etc. Under the assumption of a proportional hazards model, we propose a partial likelihood estimator to model the effect of covariates on survival via an adjusted risk set sampling procedure for when the incident cohort data is used in conjunction with the prevalent cohort data. We use simulated failure time data to validate the combined cohort proportional hazards methodology and illustrate our model using an NBA data set for career durations measured between 1990 and 2008.     

USE OF A LOG-LINEAR MODEL TO COMPUTE THE EMPIRICAL SURVIVAL CURVE FROM INTERVAL-CENSORED DATA, WITH APPLICATION TO DATA ON TESTS FOR HIV POSITIVITY

We describe how a log-linear model can be used to compute the nonparametric maximum likelihood estimate of the survival curve from interval-censored data. This permits such computation to be performed with the aid of readily available statistical software such as GLIM or SAS. The method is illustrated with reference to data from a cohort of Danish homosexual men, each of whom was tested for HIV positivity on one or more of six possible follow-up times.     

Bayesian gamma frailty models for survival data with semi-competing risks and treatment switching

Motivated from a colorectal cancer study, we propose a class of frailty semi-competing risks survival models to account for the dependence between disease progression time, survival time, and treatment switching. Properties of the proposed models are examined and an efficient Gibbs sampling algorithm using the collapsed Gibbs technique is developed. A Bayesian procedure for assessing the treatment effect is also proposed. The deviance information criterion (DIC) with an appropriate deviance function and Logarithm of the pseudomarginal likelihood (LPML) are constructed for model comparison. A simulation study is conducted to examine the empirical performance of DIC and LPML and as well as the posterior estimates. The proposed method is further applied to analyze data from a colorectal cancer study.     

Maximum Likelihood Estimation for Cox's Regression Model Under Case–Cohort Sampling

Abstract.  Case–cohort sampling aims at reducing the data sampling and costs of large cohort studies. It is therefore important to estimate the parameters of interest as efficiently as possible. We present a maximum likelihood estimator (MLE) for a case–cohort study based on the proportional hazards assumption. The estimator shows finite sample properties that improve on those by the Self & Prentice [Ann. Statist. 16 (1988)] estimator. The size of the gain by the MLE varies with the level of the disease incidence and the variability of the relative risk over the considered population. The gain tends to be small when the disease incidence is low. The MLE is found by a simple EM algorithm that is easy to implement. Standard errors are estimated by a profile likelihood approach based on EM-aided differentiation.     

Non-parametric Back-projection of HIV Positive Tests using Multinomial and Poisson Settings

Back-projection is a commonly used method in reconstructing HIV incidence. Instead of using AIDS incidence data in back-projection, this paper uses HIV positive tests data. Both multinomial and Poisson settings are used. The two settings give similar results when a parametric form or step function is assumed for the infection curve. However, this may not be true when the HIV infection in each year is characterized by a different parameter. This paper attempts to use simulation studies to compare these two settings by constructing various scenarios for the infection curve. Results show that both methods give approximately the same estimates of the number of HIV infections in the past, whilst the estimates for HIV infections in the recent past differ a lot. The multinomial setting always gives a levelling-off pattern for the recent past, while the Poisson setting is more sensitive to the change in the shape of the HIV infection curve. Nonetheless, the multinomial setting gives a relatively narrower point-wise probability interval. When the size of the epidemic is large, the narrow probability interval may be under-estimating the true underlying variation.     

Reconstructing the incidence of human immunodeficiency virus (HIV) in Hong Kong by using data from HIV positive tests and diagnoses of acquired immune deficiency syndrome

Summary. The human immunodeficiency virus–acquired immune deficiency syndrome (HIV–AIDS) epidemic in Hong Kong has been under surveillance in the form of voluntary reporting since 1984. However, there has been little discussion or research on the reconstruction of the HIV incidence curve. This paper is the first to use a modified back-projection method to estimate the incidence of HIV in Hong Kong on the basis of the number of positive HIV tests only. The model proposed has several advantages over the original back-projection method based on AIDS data only. First, not all HIV-infected individuals will develop AIDS by the time of analysis, but some of them may undertake an HIV test; therefore, the HIV data set contains more information than the AIDS data set. Second, the HIV diagnosis curve usually has a smoother pattern than the AIDS diagnosis curve, as it is not affected by redefinition of AIDS. Third, the time to positive HIV diagnosis is unlikely to be affected by treatment effects, as it is unlikely that an individual receives medication before the diagnosis of HIV. Fourth, the induction period from HIV infection to the first HIV positive test is usually shorter than the incubation period which is from HIV infection to diagnosis of AIDS. With a shorter induction period, more information becomes available for estimating the HIV incidence curve. Finally, this method requires the number of positive HIV diagnoses only, which is readily available from HIV–AIDS surveillance systems in many countries. It is estimated that, in Hong Kong, the cumulative number of HIV infections during the period 1979–2000 is about 2600, whereas an estimate based only on AIDS data seems to give an underestimate.     

Stratified proportional subdistribution hazards model with covariate-adjusted censoring weight for case-cohort studies

The case-cohort study design is widely used to reduce cost when collecting expensive covariates in large cohort studies with survival or competing risks outcomes. A case-cohort study dataset consists of two parts: (a) a random sample and (b) all cases or failures from a specific cause of interest. Clinicians often assess covariate effects on competing risks outcomes. The proportional subdistribution hazards model directly evaluates the effect of a covariate on the cumulative incidence function under the non-covariate-dependent censoring assumption for the full cohort study. However, the non-covariate-dependent censoring assumption is often violated in many biomedical studies. In this article, we propose a proportional subdistribution hazards model for case-cohort studies with stratified data with covariate-adjusted censoring weight. We further propose an efficient estimator when extra information from the other causes is available under case-cohort studies. The proposed estimators are shown to be consistent and asymptotically normal. Simulation studies show (a) the proposed estimator is unbiased when the censoring distribution depends on covariates and (b) the proposed efficient estimator gains estimation efficiency when using extra information from the other causes. We analyze a bone marrow transplant dataset and a coronary heart disease dataset using the proposed method.     

A Partial Likelihood Estimator of Vaccine Efficacy

A partial likelihood method is proposed for estimating vaccine efficacy for a general epidemic model. In contrast to the maximum likelihood estimator (MLE) which requires complete observation of the epidemic, the suggested method only requires information on the sequence in which individuals are infected and not the exact infection times. A simulation study shows that the method performs almost as well as the MLE. The method is applied to data on the infectious disease mumps.     

Analysis of interval censored failure time data with competing risk

In this article, we analyze interval censored failure time data with competing risks. A new estimator for the cumulative incidence function is derived using an approximate likelihood and a test statistic to compare two samples is then obtained by extending Sun's test statistic. Small sample properties of the proposed methods are examined by conducting simulations and a cohort dataset from AIDS patients is analyzed as a real example.     

Nonparametric inference and uniqueness for periodically observed progressive disease models

In many studies examining the progression of HIV and other chronic diseases, subjects are periodically monitored to assess their progression through disease states. This gives rise to a specific type of panel data which have been termed “chain-of-events data”; e.g. data that result from periodic observation of a progressive disease process whose states occur in a prescribed order and where state transitions are not observable. Using a discrete time semi-Markov model, we develop an algorithm for nonparametric estimation of the distribution functions of sojourn times in a J state progressive disease model. Issues of uniqueness for chain-of-events data are not well-understood. Thus, a main goal of this paper is to determine the uniqueness of the nonparametric estimators of the distribution functions of sojourn times within states. We develop sufficient conditions for uniqueness of the nonparametric maximum likelihood estimator, including situations where some but not all of its components are unique. We illustrate the methods with three examples.