Descriptive epidemiology of CNS tumors in France: results from the Gironde Registry for the period 2000-2007.

An increase in the incidence of CNS tumors has been observed in many countries in the last decades. The reality of this trend has been much debated, as it has happened during a period when computer-assisted tomography and MRI have dramatically improved the detection of these tumors. The Gironde CNS Tumor Registry provides here the first data on CNS tumor incidence and trends in France for all histological types, including benign and malignant tumors, for the period 2000-2007. Incidence rates were calculated globally and for each histological subtype. For trends, a piecewise log-linear model was used. The overall annual incidence rate was found to be 17.6/100 000. Of this rate, 7.9/100 000 were neuroepithelial tumors and 6.0/100 000 were meningiomas. An overall increase in CNS tumor incidence was observed from 2000 to 2007, with an annual percent change (APC) of +2.33%, which was explained mainly by an increase in the incidence of meningiomas over the 8-year period (APC = +5.4%), and also more recently by an increase in neuroepithelial tumors (APC = +7.45% from 2003). The overall increase was more pronounced in women and in the elderly, with an APC peaking at +24.65% in subjects 85 and over. The increase in the incidence rates we observed may have several explanations: not only improvements in registration, diagnosis, and clinical practice, but also changes in potential risk factors.

Estimation of the distribution of infection times using longitudinal serological markers of HIV: implications for the estimation of HIV incidence.

In the last decade, interest has been focused on human immunodeficiency virus (HIV) antibody assays and testing strategies that could distinguish recent infections from established infection in a single serum sample. Incidence estimates are obtained by using the relationship between prevalence, incidence, and duration of recent infection (window period). However, recent works demonstrated limitations of this approach due to the use of an estimated mean "window period." We propose an alternative approach that consists in estimating the distribution of infection times based on serological marker values at the moment when the infection is first discovered. We propose a model based on the repeated measurements of virological markers of seroconversion for the marker trajectory. The parameters of the model are estimated using data from a cohort of HIV-infected patients enrolled during primary infection. This model can be used for estimating the distribution of infection times for newly HIV diagnosed subjects reported in a HIV surveillance system. An approach is proposed for estimating HIV incidence from these results.

Number of deaths among HIV-infected adults in France in 2000, three-source capture-recapture estimation.

We estimated the number of deaths in France for the year 2000 in HIV-infected adults using three sources. The sources were (1) the 'Mortalité 2000' survey (M2000): 964 deaths were documented by 185 hospital wards involved in HIV management; (2) 1288 death certificates with a mention of HIV infection (INSERM-CepiDc) and (3) the French hospital database on HIV infection (FHDH) identified 654 deaths. The capture-recapture method was used with log-linear modelling. Overall 1559 deaths were observed. Estimation of the number of deaths in France was 1699 (95% CI 1671-1727). The completeness of M2000, CepiDc and FHDH were 55%, 76% and 38% respectively. Diversification of diseases and of causes of death in HIV-infected adults may explain: (1) the diversification of physicians involved in their management and incomplete coverage of M2000 and FHDH, and (2) why HIV infection was not mentioned in all death certificates.

Modeling recurrence in colorectal cancer.

OBJECTIVE: To assess the role of recurrence in prognosis of colon cancer, we investigated several methodologic issues, including application of classic survival analysis and Markov model. STUDY DESIGN AND SETTING: The data were recorded by the Registry of Digestive Tumors of Côte d'Or, France, for 874 patients who had been treated by surgery between 1976 and 1984 and followed for up to 11 years. Survival analyses included the Cox proportional hazards model and its two generalizations that allow recurrence to be taken into account as a time-dependent covariate or as a competing outcome. The Markov model was used to analyze simultaneously recurrence and death. RESULTS: The competing risks approach is not appropriate because censoring is indisputably informative. The Markov model and the Cox model, with recurrence as a time-dependent covariate, provided similar results, demonstrating the impact of age and gender on recurrence and revealing a reduction in the effect of site and stage on mortality. CONCLUSION: A Markov multistate model seems to give new insights about the course of digestive cancer progression and into the role of recurrence in this process.

Estimating the efficacy of interventions to prevent mother-to-child transmission of HIV in breast-feeding populations: development of a consensus methodology.

Postnatal transmission of HIV through breast milk complicates both the design of effective interventions to prevent mother-to-child transmission of HIV (PMTCT) and their evaluation. Estimated long-term efficacy in five African trials (four with peri-partum antiretrovirals and one with artificial feeding) varied from 25 to 50 per cent. This variation may be due, at least in part, to differences in analytical methodology. To facilitate direct comparison between trials, a methodological consensus approach to the analysis and presentation of the results of PMTCT trials was developed. The initial methodology used and results presented from African trials with available long-term efficacy data were reviewed during a workshop in Bordeaux, France, in September 2000. A consensus approach for evaluating efficacy applicable across PMTCT studies was developed. There are four typical situations defined by duration of follow-up (short versus long), and the available demographic (vital status) and biological data (single versus repeat HIV testing). Efficacy can be assessed from the risk of infection directly or from HIV-free survival by combining infection and death as a single endpoint. Studies should report results in a standardized format including infection, weaning, mortality and loss to follow-up. New statistical methods that account for the unknown date when a child would first test positive for HIV, for weaning as a competing risk for HIV infection, and for increased risk of death among HIV-infected children should be used in analysing data from PMTCT studies with repeat HIV testing. All estimates should be reported with confidence intervals. This standardized methodology that allows direct comparison between studies is now being applied to four randomized clinical trials.

MKVPCI: a computer program for Markov models with piecewise constant intensities and covariates.

We present a computer program for fitting Markov models with piecewise constant intensities and for estimating the effect of covariates on transition intensities. The basic idea of the proposed approach is to introduce artificial time-dependent covariates in the data to represent the time dependence of the transition intensities, and to use a modified time-homogeneous Markov model to estimate the baseline transition intensities and the regression coefficients. The program provides the maximum likelihood estimates of the parameters together with their estimated standard errors, and allows testing various statistical hypotheses. To illustrate the use of the program, we present a three-state model for analyzing the smoking habits of school children.

PHMPL: a computer program for hazard estimation using a penalized likelihood method with interval-censored and left-truncated data.

The Cox model is the model of choice when analyzing right-censored and possibly left-truncated survival data. The present paper proposes a program to estimate the hazard function in a proportional hazards model and also to treat more complex observation schemes involving general censored and left-truncated data. The hazard function estimator is defined non-parametrically as the function which maximizes a penalized likelihood, and the solution is approximated using splines. The smoothing parameter is chosen using approximate cross-validation. Confidence bands for the estimator are given. As an illustration, the age-specific incidence of dementia is estimated and one of its risk factors is studied.

Effect of gender, age, transmission category, and antiretroviral therapy on the progression of human immunodeficiency virus infection using multistate Markov models. Groupe d'Epidémiologie Clinique du SIDA en Aquitaine.

This article illustrates the use of time-homogeneous Markov models with covariates to estimate the AIDS incubation period distribution from prevalent cohorts and to evaluate the effect of factors such as gender, age, human immunodeficiency virus (HIV) transmission category, and antiretroviral therapy on disease progression. We applied this methodology to the analysis of data from a cohort of 3,027 patients enrolled from a hospital-based surveillance system of HIV infection in the Bordeaux University Hospital and four secondary public hospitals in southwestern France. A total of 998 individuals (33%) progressed to AIDS during a median follow-up period of 34 months. Based on a progressive three-state Markov model, the estimated mean and median incubation periods were 9.1 years [95% confidence interval (CI) = 8.7-9.6] and 7.5 years (95% CI = 7.2-7.9), respectively. Our analyses showed a similar disease progression in men and women; we observed a more rapid progression for older subjects compared with younger ones and for homosexual men compared with heterosexuals, intravenous drug users, and transfusion recipients, who had similar disease progression rates after adjusting for age. The use of antiretroviral therapy appeared to slow disease progression. Moreover, the results indicated that a combination therapy of zidovudine with another antiretroviral drug may be more efficient than zidovudine monotherapy.

Modelling age-specific risk: application to dementia.

We give up-to-date methods for estimating the age-specific incidence of a disease and for estimating the effect of risk factors. We recommend taking age as the basic time scale of the analysis; then, the hazard function can be interpreted as the age-specific incidence of the disease. This choice raises a delayed entry problem. We present three methods: the person-years method; the smoothed Nelson-Aalen estimator, and the penalized likelihood approach. When explanatory variables are available, the Poisson model and the Cox model with delayed entry may be used for estimating relative risks; the penalized likelihood approach can also be used. We apply these methods to estimate the age-specific incidence of dementia using data from a large cohort study, Paquid. This 5-year study followed a random initial sample of 3675 subjects with 190 incident cases of dementia. We compare the estimates based on the three possible methods. The estimated incidences computed separately for men and women cross and it is verified that a non-proportional hazards model for gender holds; women below 75 have a lower risk than men while women above 75 have a higher risk.

A proportional hazards model for arbitrarily censored and truncated data.

Turnbull (1976, Journal of Royal Statistical Society, Series B 38, 290-295) proposed a method for nonparametric estimation of the distribution function when the data are incomplete because of censoring and truncation. However, as noted by Frydman (1994, Journal of Royal Statistical society, Series B 56, 71-74), Turnbull's method has to be modified to accommodate both truncation and censoring. This paper presents a detailed correction of Turnbull's method and an extension to the regression analysis: a method of fitting the proportional hazards model for arbitrarily censored and truncated data is developed. The method allows partial testing for zero regression coefficients. The test can be performed using the likelihood ratio test or the Wald test. The methodology is applied to estimate the distribution of the induction time of patients diagnosed with transfusion-associated AIDS and to estimate the distribution of time from diabetes onset to development of diabetic nephropathy for insulin-dependent diabetics.

A direct approach for correcting AIDS incidence: variance formula and comparison with other methods.

We present a direct approach for correcting the acquired immunodeficiency syndrome (AIDS) incidence data for reporting delays, based on a non-parametric method for the analysis of right truncated data. We show that the proposed method when applied for grouped data is equivalent to three other published methods. We give a simple formula for the variance of the estimated AIDS incidence. Both estimator and variance are assessed in a simulation study. It is important for the estimation of AIDS incidence in the last quarter of the period under consideration to use month rather than quarter or half-year as the time unit for the analyses. The method is illustrated using data from the United States Centers for Disease Control.

Estimating the incubation period of paediatric AIDS in Rwanda.

OBJECTIVE: To estimate the distribution of the incubation period of paediatric AIDS in Rwanda. DESIGN: Data were collected between February 1984 and December 1990 at the Centre Hospitalier de Kigali (CHK), the capital city of Rwanda, Central Africa. PATIENTS: We used a sample of 685 AIDS cases registered consecutively in the Department of Paediatrics of the CHK, in which the proportion of perinatally acquired HIV-1 infection was estimated to be 98.6%. METHODS: We performed both non-parametric and parametric analyses. The methods of estimation were adapted to truncated data, using essentially the same methods as Auger et al. in their analysis of data from the New York City and the New York State AIDS case registries in 1988. RESULTS: We found that a double Weibull model fitted the data very well and that the risk of developing AIDS was high for subjects under 18 months of age, but lower for older subjects. CONCLUSIONS: Our results were qualitatively similar to those of Auger et al.. There were quantitative differences between the two studies, but it was not possible to compare median survival periods. Parameters such as median or mean survival times cannot be validly estimated using only data from registers because these data exclude infected subjects who have not yet developed AIDS.

PIP: The authors used nonparametric and parametric methods and data on 685 AIDS cases at the Centre Hospitalier de Kigali, collected between February 1984 and December 1990, to estimate the distribution of pediatric AIDS in Kigali, Rwanda. 98.6% of the cases probably acquired AIDS via vertical transmission. A combination of the 2 Weibul distributions (parametric method) resulted in a good fit, suggesting that the sample population consisted of a subpopulation with a short incubation period and an other with a longer incubation period. The researchers could not deduce proof of heterogeneity from the shape of the distribution, however. The probability of developing AIDS during the first year of life was 0.29, which corresponded with that of the European Collaborative Study (0.26). The risk of developing pediatric AIDS increased considerably for children less than 18 months old but fell and became constant for older children. The qualitative findings matched those of a study in New York City. Even though quantitative differences between this study and the other study existed, the researchers could not compare median survival times. Since data from registers did not include HIV-infected children who had not yet developed AIDS, the researchers were not able to estimate median and mean survival periods. A possible source of bias was that the data were from a surveillance system based on cases at just 1 hospital, which probably did not see all pediatric AIDS cases. In conclusion, truncated data determined rather well the distribution of incubation periods, but could not provide much information about the scale parameters of the model.