Backcalculation of flexible linear models of the human immunodeficiency virus infection curve

The authors present a regression approach to the backcalculation of flexible linear models of the HIV infection curve. They note that "because expected AIDS incidence can be expressed as a linear function of unknown parameters, regression methods may be used to obtain parameter and covariance estimates for a variety of interesting quantities, such as the expected number of people infected in previous time intervals and the projected AIDS incidence in future time intervals. We exploit these ideas to show that estimates based on maximum likelihood are, for practical purposes, equivalent to approximate estimates based on quasi-likelihood and on Poisson regression. These algorithms are readily implemented on a personal computer." These concepts are illustrated by projecting AIDS incidence in the United States up to 1993.     

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.     

ANALYSIS OF DOUBLY CENSORED DATA AND THE HIV INCUBATION PERIOD DISTRIBUTION IN WESTERN AUSTRALIA

The paper analyses the distribution of times from HIV seroconversion to the first AIDS defining illness for a subcohort of the Western Australian HIV Cohort Study for whom the seroconversion date is known to fall within a calendar time window. The analysis is based on a generalised gamma model for the incubation times and a piecewise constant distribution for the conditional times of seroconversion given the seroconversion windows. This allows flexible hazard shapes and also allows comparison of goodness of fit of the gamma and Weibull distributions which are often used for modelling incubation times. Computational issues are discussed. In these data, neither age at seroconversion, nor calendar time of seroconversion, nor the identification of a seroconversion illness appears to afFect incubation distributions. The Weibull distribution appears to provide a reasonable fit. The distribution of times from seroconversion to an HIV-related death is also briefly considered.     

Joint models for mixed categorical outcomes: a study of HIV risk perception and disease status in Mozambique

Two types of bivariate models for categorical response variables are introduced to deal with special categories such as ‘unsure’ or ‘unknown’ in combination with other ordinal categories, while taking additional hierarchical data structures into account. The latter is achieved by the use of different covariance structures for a trivariate random effect. The models are applied to data from the INSIDA survey, where interest goes to the effect of covariates on the association between HIV risk perception (quadrinomial with an ‘unknown risk’ category) and HIV infection status (binary). The final model combines continuation-ratio with cumulative link logits for the risk perception, together with partly correlated and partly shared trivariate random effects for the household level. The results indicate that only age has a significant effect on the association between HIV risk perception and infection status. The proposed models may be useful in various fields of application such as social and biomedical sciences, epidemiology and public health.     

A Class of Non-Gaussian State Space Models With Exact Likelihood Inference

The likelihood function of a general nonlinear, non-Gaussian state space model is a high-dimensional integral with no closed-form solution. In this article, I show how to calculate the likelihood function exactly for a large class of non-Gaussian state space models that include stochastic intensity, stochastic volatility, and stochastic duration models among others. The state variables in this class follow a nonnegative stochastic process that is popular in econometrics for modeling volatility and intensities. In addition to calculating the likelihood, I also show how to perform filtering and smoothing to estimate the latent variables in the model. The procedures in this article can be used for either Bayesian or frequentist estimation of the model’s unknown parameters as well as the latent state variables. Supplementary materials for this article are available online.     

On the assessment of various factors effecting the improvement in CD4 count of aids patients undergoing antiretroviral therapy using generalized Poisson regression

An important marker for identifying the progression of human immunodeficiency virus (HIV) infection in an individual is the CD4 cell count. Antiretroviral therapy (ART) is a treatment for HIV/AIDS (AIDS, acquired immune-deficiency syndrome) which prolongs and improves the lives of patients by improving the CD4 cell count and strengthen the immune system. This strengthening of the immune system in terms of CD4 count, not only depends on various biological factors, but also other behavioral factors. Previous studies have shown the effect of CD4 count on the mortality, but nobody has attempted to study the factors which are likely to influence the improvement in CD4 count of patients diagnosed of AIDS and undergoing ART. In this paper, we use Poisson regression model (GPR) for exploring the effect of various socio-demographic covariates such as age, gender, geographical location, and drug usage on the improvement in the CD4 count of AIDS patients. However, if the CD4 count data suffers from under or overdispersion, we use GPR model and compare it with negative binomial distribution. Finally, the model is applied for the analysis of data on patients undergoing the ART in the Ram Manohar Lohia Hospital, Delhi, India. The data exhibited overdispersion and hence, GPR model provided the best fit.     

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.     

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 unknown parameters in nonlinear and non-Gaussian state-space models

For the last decade, various simulation-based nonlinear and non-Gaussian filters and smoothers have been proposed. In the case where the unknown parameters are included in the nonlinear and non-Gaussian system, however, it is very difficult to estimate the parameters together with the state variables, because the state-space model includes a lot of parameters in general and the simulation-based procedures are subject to the simulation errors or the sampling errors. Therefore, clearly, precise estimates of the parameters cannot be obtained (i.e., the obtained estimates may not be the global optima). In this paper, an attempt is made to estimate the state variables and the unknown parameters simultaneously, where the Monte Carlo optimization procedure is adopted for maximization of the likelihood function.     

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.     

Hybrid Bayesian inference on HIV viral dynamic models

Modelling of HIV dynamics in AIDS research has greatly improved our understanding of the pathogenesis of HIV-1 infection and guided for the treatment of AIDS patients and evaluation of antiretroviral therapies. Some of the model parameters may have practical meanings with prior knowledge available, but others might not have prior knowledge. Incorporating priors can improve the statistical inference. Although there have been extensive Bayesian and frequentist estimation methods for the viral dynamic models, little work has been done on making simultaneous inference about the Bayesian and frequentist parameters. In this article, we propose a hybrid Bayesian inference approach for viral dynamic nonlinear mixed-effects models using the Bayesian frequentist hybrid theory developed in Yuan [Bayesian frequentist hybrid inference, Ann. Statist. 37 (2009), pp. 2458–2501]. Compared with frequentist inference in a real example and two simulation examples, the hybrid Bayesian approach is able to improve the inference accuracy without compromising the computational load.     

The influence of behavioural heterogeneity on the population level effect of potential prophylactic human immunodeficiency virus type 1 vaccines

Theoretical results indicate that extensive coverage with low efficacy type 1 human immunodeficiency virus (HIV) vaccines could substantially reduce the incidence of HIV in developing countries. There is a non-linear relationship between effective vaccine coverage and HIV prevalence such that improved efficacy brings diminishing returns. The relative contribution of HIV-associated mortality and behavioural heterogeneity to this non-linear relationship is explored using deterministic mathematical models. If the duration of risk of acquiring HIV is long relative to the HIV incubation period then infection-associated mortality can generate the non-linear relationship. However, in its absence the same relationship results from behavioural heterogeneity. Models of HIV vaccination alongside other interventions generate qualitative results that suggest that targeted interventions lead to less redundancy in control efforts.     

A Bayesian approach for estimating antiviral efficacy in HIV dynamic models

The study of HIV dynamics is one of the most important developments in recent AIDS research. It has led to a new understanding of the pathogenesis of HIV infection. Although important findings in HIV dynamics have been published in prestigious scientific journals, the statistical methods for parameter estimation and model-fitting used in those papers appear surprisingly crude and have not been studied in more detail. For example, the unidentifiable parameters were simply imputed by mean estimates from previous studies, and important pharmacological/clinical factors were not considered in the modelling. In this paper, a viral dynamic model is developed to evaluate the effect of pharmacokinetic variation, drug resistance and adherence on antiviral responses. In the context of this model, we investigate a Bayesian modelling approach under a non-linear mixed-effects (NLME) model framework. In particular, our modelling strategy allows us to estimate time-varying antiviral efficacy of a regimen during the whole course of a treatment period by incorporating the information of drug exposure and drug susceptibility. Both simulated and real clinical data examples are given to illustrate the proposed approach. The Bayesian approach has great potential to be used in many aspects of viral dynamics modelling since it allow us to fit complex dynamic models and identify all the model parameters. Our results suggest that Bayesian approach for estimating parameters in HIV dynamic models is flexible and powerful.     

Acquired immune deficiency syndrome predictions for England and Wales (1992-97): sensitivity analysis,information, decision

Some implications of the use of the back-calculation method for estimating future trends in HIV infections and AIDS incidence in England and Wales are explored. "This paper explores in...detail some aspects of the latest projections which have only been hinted at in the report published by the Public Health Laboratory Service in 1993. The value of additional information on the HIV epidemic in discriminating between different, otherwise equally plausible, scenarios is demonstrated. The role of the backcalculation approach in determining whether, and how, the incubation distribution has been affected by increased uptake of pre-AIDS prophylaxis and treatment is discussed."     

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.     

Simultaneous tests for homogeneity of two zero-inflated (beta) populations

ABSTRACT

Motivated by an example in marine science, we use Fisher’s method to combine independent likelihood ratio tests (LRTs) and asymptotic independent score tests to assess the equivalence of two zero-inflated Beta populations (mixture distributions with three parameters). For each test, test statistics for the three individual parameters are combined into a single statistic to address the overall difference between the two populations. We also develop non parametric and semiparametric permutation-based tests for simultaneously comparing two or three features of unknown populations. Simulations show that the likelihood-based tests perform well for large sample sizes and that the statistics based on combining LRT statistics outperforms the ones based on combining score test statistics. The permutation-based tests have overall better performance in terms of both power and type I error rate. Our methods are easy to implement and computationally efficient, and can be expanded to more than two populations and to other multiple parameter families. The permutation tests are entirely generic and can be useful in various applications dealing with zero (or other) inflation.     

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.     

Comparison of Mixed-Effects Models for Skew-Normal Responses with an Application to AIDS Data: A Bayesian Approach

The potency of antiretroviral agents in AIDS clinical trials can be assessed on the basis of a viral response such as viral decay rate or change in viral load (number of HIV RNA copies in plasma). Linear, nonlinear, and nonparametric mixed-effects models have been proposed to estimate such parameters in viral dynamic models. However, there are two critical questions that stand out: whether these models achieve consistent estimates for viral decay rates, and which model is more appropriate for use in practice. Moreover, one often assumes that a model random error is normally distributed, but this assumption may be unrealistic, obscuring important features of within- and among-subject variations. In this article, we develop a skew-normal (SN) Bayesian linear mixed-effects (SN-BLME) model, an SN Bayesian nonlinear mixed-effects (SN-BNLME) model, and an SN Bayesian semiparametric nonlinear mixed-effects (SN-BSNLME) model that relax the normality assumption by considering model random error to have an SN distribution. We compare the performance of these SN models, and also compare their performance with the corresponding normal models. An AIDS dataset is used to test the proposed models and methods. It was found that there is a significant incongruity in the estimated viral decay rates. The results indicate that SN-BSNLME model is preferred to the other models, implying that an arbitrary data truncation is not necessary. The findings also suggest that it is important to assume a model with an SN distribution in order to achieve reasonable results when the data exhibit skewness.     

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.     

Approximate variance formulas and asymptotic joint sampling distributions of standardized risk ratios in the presence of competing risks in cohort studies

The present paper is concerned with some results in cohort studies, in which the individuals in two study population are exposed simultaneously to several risks of death, which compete for their lives.

The morality experience of individuals in the two study populations is compared with respect to the morality experience of individuals in a well-defined and fixed population called the standard population.

Under some reasonable assumptions, not only simple variance formulas are-developed for the standardized risk ratio statistics (S[Rcirc]R_i) but also their joint asymptotic sampling distribution. It is demonstrated that these SRcirc;R_i's have asymptotically a multivariate normal distribtion corresponding to any given number of competing risks of death, These results are utilized to construct Scheffé-type and Sidak-type simultaneous confidence intervals for the SRR_i parameters which hold regardless of any covariance structure among the competing risks of death. The corresponding results for the cause-specific SMR and the externally standardized risk ratio parameters follow as special cases.

The present paper generalizes the available results in the literature in two directions, namely, to obtain simple variance formulas for the S[Rcirc]R_i, statistics and to treat the situation in the presence of competing risks to which individuals in a study are simultaneously exposed.

An empirical evaluation of these results is discussed in the last section utilizing some real cohort data from two recent occupational epidemiologic cohort studies.