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.     

A multistate approach for estimating the incidence of human immunodeficiency virus by using data from a prevalent cohort study

Summary.  Cohort studies of individuals infected with the human immunodeficiency virus (HIV) provide useful information on the past pattern of HIV diagnoses, progression of the disease and use of antiretroviral therapy. We propose a new method for using individual data from an open prevalent cohort study to estimate the incidence of HIV, by jointly modelling the HIV diagnosis, the inclusion in the cohort and the progression of the disease in a Markov model framework. The estimation procedure involves the construction of a likelihood function which takes into account the probability of observing the total number of subjects who are enrolled in the cohort and the probabilities of passage through the stages of disease for each observed subject conditionally on being included in the cohort. The estimator of the HIV infection rate is defined as the function which maximizes a penalized likelihood, and the solution of this maximization problem is approximated on a basis of cubic M -splines. The method is illustrated by using cohort data from a hospital-based surveillance system of HIV infection in Aquitaine, a region of south-western France. A simulation study is performed to study the ability of the model to reconstruct the incidence of HIV from prevalent cohort data.     

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.     

A frailty model for (interval) censored family survival data,applied to the age at onset of non-physical problems

Family survival data can be used to estimate the degree of genetic and environmental contributions to the age at onset of a disease or of a specific event in life. The data can be modeled with a correlated frailty model in which the frailty variable accounts for the degree of kinship within the family. The heritability (degree of heredity) of the age at a specific event in life (or the onset of a disease) is usually defined as the proportion of variance of the survival age that is associated with genetic effects. If the survival age is (interval) censored, heritability as usually defined cannot be estimated. Instead, it is defined as the proportion of variance of the frailty associated with genetic effects. In this paper we describe a correlated frailty model to estimate the heritability and the degree of environmental effects on the age at which individuals contact a social worker for the first time and to test whether there is a difference between the survival functions of this age for twins and non-twins.     

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.     

On the incidence–prevalence relation and length‐biased sampling

For many diseases, logistic constraints render large incidence studies difficult to carry out. This becomes a drawback, particularly when a new study is needed each time the incidence rate is investigated in a new population. By carrying out a prevalent cohort study with follow‐up it is possible to estimate the incidence rate if it is constant. The authors derive the maximum likelihood estimator (MLE) of the overall incidence rate, λ, as well as age‐specific incidence rates, by exploiting the epidemiologic relationship, (prevalence odds) = (incidence rate) × (mean duration) (P/[1 ? P] = λ × µ). The authors establish the asymptotic distributions of the MLEs and provide approximate confidence intervals for the parameters. Moreover, the MLE of λ is asymptotically most efficient and is the natural estimator obtained by substituting the marginal maximum likelihood estimators for P and µ into P/[1 ? P] = λ × µ. Following‐up the subjects allows the authors to develop these widely applicable procedures. The authors apply their methods to data collected as part of the Canadian Study of Health and Ageing to estimate the incidence rate of dementia amongst elderly Canadians. The Canadian Journal of Statistics © 2009 Statistical Society of Canada     

Parametric modelling of prevalent cohort data with uncertainty in the measurement of the initial onset date

In prevalent cohort studies with follow-up, if disease duration is the focus, the date of onset must be obtained retrospectively. For some diseases, such as Alzheimer’s disease, the very notion of a date of onset is unclear, and it can be assumed that the reported date of onset acts only as a proxy for the unknown true date of onset. When adjusting for onset dates reported with error, the features of left-truncation and potential right-censoring of the failure times must be modeled appropriately. Under the assumptions of a classical measurement error model for the onset times and an underlying parametric failure time model, we propose a maximum likelihood estimator for the failure time distribution parameters which requires only the observed backward recurrence times. Costly and time-consuming follow-up may therefore be avoided. We validate the maximum likelihood estimator on simulated datasets under varying parameter combinations and apply the proposed method to the Canadian Study of Health and Aging dataset.

     

Model diagnostics for the proportional hazards model with length-biased data

Length-biased data are frequently encountered in prevalent cohort studies. Many statistical methods have been developed to estimate the covariate effects on the survival outcomes arising from such data while properly adjusting for length-biased sampling. Among them, regression methods based on the proportional hazards model have been widely adopted. However, little work has focused on checking the proportional hazards model assumptions with length-biased data, which is essential to ensure the validity of inference. In this article, we propose a statistical tool for testing the assumed functional form of covariates and the proportional hazards assumption graphically and analytically under the setting of length-biased sampling, through a general class of multiparameter stochastic processes. The finite sample performance is examined through simulation studies, and the proposed methods are illustrated with the data from a cohort study of dementia in Canada.

     

The analysis of incomplete data using stochastic covariates

In the development of many diseases there are often associated random variables which continuously reflect the progress of a subject towards the final expression of the disease (failure). At any given time these processes, which we call stochastic covariates, may provide information about the current hazard and the remaining time to failure. Likewise, in situations when the specific times of key prior events are not known, such as the time of onset of an occult tumour or the time of infection with HIV-1, it may be possible to identify a stochastic covariate which reveals, indirectly, when the event of interest occurred. The analysis of carcinogenicity trials which involve occult tumours is usually based on the time of death or sacrifice and an indicator of tumour presence for each animal in the experiment. However, the size of an occult tumour observed at the endpoint represents data concerning tumour development which may convey additional information concerning both the tumour incidence rate and the rate of death to which tumour-bearing animals are subject. We develop a stochastic model for tumour growth and suggest different ways in which the effect of this growth on the hazard of failure might be modelled. Using a combined model for tumour growth and additive competing risks of death, we show that if this tumour size information is used, assumptions concerning tumour lethality, the context of observation or multiple sacrifice times are no longer necessary in order to estimate the tumour incidence rate. Parametric estimation based on the method of maximum likelihood is outlined and is applied to simulated data from the combined model. The results of this limited study confirm that use of the stochastic covariate tumour size results in more precise estimation of the incidence rate for occult tumours.     

Random regression models for human immunodeficiency virus ribonucleic acid data subject to left censoring and informative drop-outs

Objectives in many longitudinal studies of individuals infected with the human immunodeficiency virus (HIV) include the estimation of population average trajectories of HIV ribonucleic acid (RNA) over time and tests for differences in trajectory across subgroups. Special features that are often inherent in the underlying data include a tendency for some HIV RNA levels to be below an assay detection limit, and for individuals with high initial levels or high ranges of change to drop out of the study early because of illness or death. We develop a likelihood for the observed data that incorporates both of these features. Informative drop-outs are handled by means of an approach previously published by Schluchter. Using data from the HIV Epidemiology Research Study, we implement a maximum likelihood procedure to estimate initial HIV RNA levels and slopes within a population, compare these parameters across subgroups of HIV-infected women and illustrate the importance of appropriate treatment of left censoring and informative drop-outs. We also assess model assumptions and consider the prediction of random intercepts and slopes in this setting. The results suggest that marked bias in estimates of fixed effects, variance components and standard errors in the analysis of HIV RNA data might be avoided by the use of methods like those illustrated.     

BACKWARD ESTIMATION OF STOCHASTIC PROCESSES WITH FAILURE EVENTS AS TIME ORIGINS

Stochastic processes often exhibit sudden systematic changes in pattern a short time before certain failure events. Examples include increase in medical costs before death and decrease in CD4 counts before AIDS diagnosis. To study such terminal behavior of stochastic processes, a natural and direct way is to align the processes using failure events as time origins. This paper studies backward stochastic processes counting time backward from failure events, and proposes one-sample nonparametric estimation of the mean of backward processes when follow-up is subject to left truncation and right censoring. We will discuss benefits of including prevalent cohort data to enlarge the identifiable region and large sample properties of the proposed estimator with related extensions. A SEER-Medicare linked data set is used to illustrate the proposed methodologies.     

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.     

Estimation of the joint survival function for successive duration times under double-truncation and right-censoring

ABSTRACT

In incident cohort studies, survival data often include subjects who have had an initiate event at recruitment and may potentially experience two successive events (first and second) during the follow-up period. When disease registries or surveillance systems collect data based on incidence occurring within a specific calendar time interval, the initial event is usually subject to double truncation. Furthermore, since the second duration process is observable only if the first event has occurred, double truncation and dependent censoring arise. In this article, under the two sampling biases with an unspecified distribution of truncation variables, we propose a nonparametric estimator of the joint survival function of two successive duration times using the inverse-probability-weighted (IPW) approach. The consistency of the proposed estimator is established. Based on the estimated marginal survival functions, we also propose a two-stage estimation procedure for estimating the parameters of copula model. The bootstrap method is used to construct confidence interval. Numerical studies demonstrate that the proposed estimation approaches perform well with moderate sample sizes.     

Estimation of prolongation of hospital stay attributable to nosocomial infections: New approaches based on multistate models

Evaluation of the impact of nosocomial infection on duration of hospital stay usually relies on estimates obtained in prospective cohort studies. However, the statistical methods used to estimate the extra length of stay are usually not adequate. A naive comparison of duration of stay in infected and non-infected patients is not adequate to estimate the extra hospitalisation time due to nosocomial infections. Matching for duration of stay prior to infection can compensate in part for the bias of ad hoc methods. New model-based approaches have been developed to estimate the excess length of stay. It will be demonstrated that statistical models based on multivariate counting processes provide an appropriate framework to analyse the occurrence and impact of nosocomial infections. We will propose and investigate new approaches to estimate the extra time spent in hospitals attributable to nosocomial infections based on functionals of the transition probabilities in multistate models. Additionally, within the class of structural nested failure time models an alternative approach to estimate the extra stay due to nosocomial infections is derived. The methods are illustrated using data from a cohort study on 756 patients admitted to intensive care units at the University Hospital in Freiburg.     

A three-state continuous time Markov chain model for HIV disease burden

Plasma HIV viral load (VL) is the clinical indicator used to evaluate disease burden for HIV-infected patients. We developed a covariate-adjusted, three-state, homogenous continuous time Markov chain model for HIV/AIDS disease burden among subgroups. We defined Detectable and Undetectable HIV VL levels as two transient states and Death as the third absorbing state. We implemented the exact maximum likelihood method to estimate the parameters with related asymptotic distribution to conduct hypothesis testing. We evaluated the proposed model using HIV-infected individuals from South Carolina (SC) HIV surveillance data. Using the developed model, we estimated and compared the transition hazards, transition probabilities, and the state-specific duration for HIV-infected individuals. We examined gender, race/ethnicity, age, CD4 count, place of residence, and antiretroviral treatment regimen prescribed at the beginning of the study period. We found that patients with a higher CD4 count, increased age, heterosexual orientation, white, and single tablet regimen users were associated with reduced risk of transitioning to a Detectable VL from an Undetectable VL, whereas shorter time since diagnosis, being male, and injection drug use increased the risk of the same transition.     

Clustered Survival Data with Left‐truncation

Left‐truncation occurs frequently in survival studies, and it is well known how to deal with this for univariate survival times. However, there are few results on how to estimate dependence parameters and regression effects in semiparametric models for clustered survival data with delayed entry. Surprisingly, existing methods only deal with special cases. In this paper, we clarify different kinds of left‐truncation and suggest estimators for semiparametric survival models under specific truncation schemes. The large‐sample properties of the estimators are established. Small‐sample properties are investigated via simulation studies, and the suggested estimators are used in a study of prostate cancer based on the Finnish twin cohort where a twin pair is included only if both twins were alive in 1974.     

Measures of mortality in the study of individuals infected with the human immunodeficiency virus in the UK haemophilia population

Two statistical issues that have arisen in the course of a study of mortality and disease related to the human immunodeficiency virus (HIV) in the haemophilia population of the UK are discussed. The first of these concerns methods of standardization for age and it is shown that, when the mortality of HIV-infected individuals with different severities of haemophilia are compared, an analysis based on the ratio of observed to national expected deaths suggests that mortality in HIV-infected individuals depends on the severity of their haemophilia. This conclusion is inappropriate and mortality in HIV-infected individuals is, in fact, similar regardless of severity of haemophilia. The second part of the paper discusses the effect of using various end points for studies of survival and progression of HIV-related disease. In the present example it was possible to calculate relative survival in HIV-infected individuals, i.e. survival after correcting for mortality expected in the absence of HIV infection. An analysis based on absolute survival gave a very similar picture of the effect of age at infection to an analysis based on relative survival, whereas an analysis based on the time to diagnosis of acquired immune deficiency syndrome (AIDS) underestimated the effect substantially and the possible alternative end point of time to AIDS or HIV-related death was shown to be subject to considerable misclassification error.     

Variable selection and prediction in biased samples with censored outcomes

With the increasing availability of large prospective disease registries, scientists studying the course of chronic conditions often have access to multiple data sources, with each source generated based on its own entry conditions. The different entry conditions of the various registries may be explicitly based on the response process of interest, in which case the statistical analysis must recognize the unique truncation schemes. Moreover, intermittent assessment of individuals in the registries can lead to interval-censored times of interest. We consider the problem of selecting important prognostic biomarkers from a large set of candidates when the event times of interest are truncated and right- or interval-censored. Methods for penalized regression are adapted to handle truncation via a Turnbull-type complete data likelihood. An expectation–maximization algorithm is described which is empirically shown to perform well. Inverse probability weights are used to adjust for the selection bias when assessing predictive accuracy based on individuals whose event status is known at a time of interest. Application to the motivating study of the development of psoriatic arthritis in patients with psoriasis in both the psoriasis cohort and the psoriatic arthritis cohort illustrates the procedure.     

Forward and Backward Recurrence Times and Length Biased Sampling: Age Specific Models

Consider a chronic disease process which is beginning to be observed at a point in chronological time. The backward recurrence and forward recurrence times are defined for prevalent cases as the time with disease and the time to leave the disease state, respectively, where the reference point is the point in time at which the disease process is being observed. In this setting the incidence of disease affects the recurrence time distributions. In addition, the survival of prevalent cases will tend to be greater than the population with disease due to length biased sampling. A similar problem arises in models for the early detection of disease. In this case the backward recurrence time is how long an individual has had disease before detection and the forward recurrence time is the time gained by early diagnosis, i.e., until the disease becomes clinical by exhibiting signs or symptoms. In these examples the incidence of disease may be age related resulting in a non-stationary process. The resulting recurrence time distributions are derived as well as some generalization of length-biased sampling.