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Background The quality of the data collected is essential for the credibility of the results of clinical trials. Centralized statistical monitoring (CSM) has been proposed to quickly identify one study center in which the distribution of a variable is atypical, prompting on-site confirmation of the problem and correction as necessary. The ideal CSM method should allow early detection of a problem and therefore involve the fewest possible participants. Methods We simulated clinical trials and compared the performance of four CSM methods (Student, Desmet, Hatayama, Distance) to detect whether the distribution of a quantitative variable was atypical in one center in relation to the others, with different numbers of participants and different mean deviation amplitudes. Results The Desmet and Distance methods had low sensitivity for low mean-deviation values but very high specificity for detecting all deviations of the mean (including small values). The Student and Hatayama methods had higher sensitivity for low mean-deviation values but very low specificity for detecting all deviations of the mean. Increasing the number of participants in the atypical center, or increasing the ratio of the number of participants in the atypical center to the number of participants in the study, did not fundamentally alter the findings. Conclusion Although the Student and Hatayama methods are more sensitive, their low specificity would lead to too many alerts being triggered, which would result in additional unnecessary control work to ensure data quality. The Desmet and Distance methods have low sensitivity when the deviation from the mean is low, suggesting that the CSM should be used alongside other conventional monitoring procedures rather than replacing them. However, they have excellent specificity, which suggests they can be applied routinely, since using them takes up no time at central level and does not cause any unnecessary workload in investigating centers.

Since the discovery of the human immunodeficiency virus (HIV) 35 years ago, the epidemic is still ongoing in France. To monitor the dynamics of HIV transmission and assess the impact of prevention campaigns, the main indicator is the incidence. One method to estimate the HIV incidence is based on biomarker values at diagnosis and their dynamics over time. Estimating the HIV incidence from biomarkers first requires modeling their dynamics since infection using external longitudinal data. The objective of the work presented here is to estimate the joint dynamics of two biomarkers from the PRIMO cohort. We thus jointly modeled the dynamics of two biomarkers (TM and V3) using a multi-response nonlinear mixed-effect model. The parameters were estimated using Bayesian Hamiltonian Monte Carlo inference. This procedure was first applied to the real data of the PRIMO cohort. In a simulation study, we then evaluated the performance of the Bayesian procedure for estimating the parameters of multi-response nonlinear mixed-effect models.

International audience; OBJECTIVES:Mental health is a largely neglected issue among in Sub-Saharan Africa, especially among key populations at risk for HIV. The aim of this study was to estimate the prevalence of psychological distress (PD) and to assess the factors associated among males who have sex with males (MSM), female sex workers (FSW) and drug users (DU) in Togo in 2017.STUDY DESIGN:A cross-sectional bio-behavioral study was conducted in August and September 2017 using a respondent-driven sampling (RDS) method, in eight cities in Togo.METHODS:A standardized questionnaire was used to record sociodemographic characteristics and sexual behaviors. The Alcohol Use Disorders Identification Test (AUDIT) and a subset of questions from the Tobacco Questions for Survey were used to assess alcohol and tobacco consumption respectively. PD was assessed with the Kessler Psychological Distress Scale. A blood sample was taken to test for HIV. Descriptive statistics, univariable and multivariable ordinal regression models were used for analysis.RESULTS:A total of 2044 key populations including 449 DU, 952 FSW and 643 MSM with a median age of 25 years, interquartile range (IQR) [21-32] were recruited. The overall prevalence of mild PD among the three populations was 19.9% (95%CI = [18.3-21.8]) and was 19.2% (95%CI = [17.5-20.9]) for severe/moderate PD. HIV prevalence was 13.7% (95%CI = [12.2-15.2]). High age (≥ 25 years) [aOR = 1.24 (95% CI: 1.02-1.50)], being HIV positive [aOR = 1.80 (95% CI: 1.31-2.48)] and hazardous alcohol consumption [aOR = 1.52 (95% CI: 1.22-1.87)] were risk factors for PD. Secondary [aOR = 0.52 (95% CI: 0.42-0.64)] or higher [aOR = 0.46 (95% CI: 0.32-0.64)] education levels were protective factors associated with PD. FSW [OR = 0.55 (95% CI: 0.43-0.68)] and MSM [OR = 0.33 (95% CI: 0.24-0.44)] were less likely to report PD compared with DU.CONCLUSION AND RECOMMENDATIONS:This is the first study conducted among a large, nationally representative sample of key populations in Togo. The prevalence of PD is high among these populations in Togo and was associated to HIV infection. The present study indicates that mental health care must be integrated within health programs in Togo with a special focus to key populations through interventions such as social support groups.

France has not prohibited all forms of corporal punishment, and the point at which an act is regarded as physical abuse is not clearly determined. The aim of our study was to compare perception of a caregiver’s violent behavior toward his child by professionals and parents in an emergency department and determine characteristics associated with that perception. A cross-sectional study was conducted from November 2013 to October 2014 in the emergency department of the pediatric university hospital in Bordeaux, France. An anonymous self-administered questionnaire, including vignettes describing hypothetical situations of violent interaction between a parent and child, and items related to sociodemographic and family characteristics, was administered to professionals and parents. Vignettes included varying child’s age and behavior, frequency of caregiver’s behavior, hitting with/without an object, and targeted child’s body part. Violent behavior was restricted to hitting for reasons of feasibility. Respondents were asked to rate the acceptability of situations on a 100-mm visual analog scale. Analyses were multivariate mixed Poisson regressions. A total of 1,001 participants assessed the vignettes. Participants were predominantly females (64%), married or living with a partner (87%), with a median age of 34 years. Professionals assessed vignettes as acceptable significantly more than parents (mean rating 2.8 times higher; p < .001). For both professionals and parents, all vignette characteristics were significantly associated with acceptability. Parents who had a child below 1 year old, those who had visited an emergency department many times in the past year, and those who had fewer children were less tolerant. Such findings indicate the need for additional research to better appreciate consequences and severity of violent behavior toward children, and the need to educate parents and professionals.

Methods of calculation of mother-to-child transmission probabilities and live births rate among HIV positive women. This additional file is a .docx file which contains description of mathematical models used to estimate mother-to-child transmission probabilities. It is also described here how live births rate among HIV positive women were calculated. (DOCX 37 kb)

Prognostic studies often have to deal with two important challenges: (i) separating effects of predictions on different 'competing' events and (ii) uncertainty about cause of death. Multistate Markov models permit multivariable analyses of competing risks of, for example, mortality versus disease recurrence. On the other hand, relative survival methods help estimate disease-specific mortality risks even in the absence of data on causes of death. In this paper, we propose a new Markov relative survival (MRS) model that attempts to combine these two methodologies. Our MRS model extends the existing multistate Markov piecewise constant intensities model to relative survival modeling. The intensity of transitions leading to death in the MRS model is modeled as the sum of an estimable excess hazard of mortality from the disease of interest and an 'offset' defined as the expected hazard of all-cause 'natural' mortality obtained from relevant life-tables. We evaluate the new MRS model through simulations, with a design based on registry-based prognostic studies of colon cancer. Simulation results show almost unbiased estimates of prognostic factor effects for the MRS model. We also applied the new MRS model to reassess the role of prognostic factors for mortality in a study of colorectal cancer. The MRS model considerably reduces the bias observed with the conventional Markov model that does not permit accounting for unknown causes of death, especially if the 'true' effects of a prognostic factor on the two types of mortality differ substantially.

Objectives Interurban roads account for a significant proportion of traffic deaths in developing countries. In this pilot study, hazard perceptions of interurban road sites involved in ≥3 injury road traffic crashes were compared with those not involved in road traffic crashes on the same road sections. Settings Karachi–Hala (Pakistan) and Yaounde–Douala (Cameroon) road sections were the main study settings. Data Videos of 26 high-risk sites and 26 low-risk sites from Karachi–Hala (Pakistan) and Yaounde–Douala (Cameroon) roads, matched for the road section, were shown to 100 voluntary Pakistani drivers. Variations in perceived site hazardousness and preferred speed for each site pair were assessed. Analyses Factors associated with incorrect hazard perception of high-risk sites (perceived as safe) were assessed by multinomial logistic regression analyses. Results Drivers reported a higher hazard perception and a lower preferred speed for high-risk sites than for their matched low-risk sites in less than half of pairs (n=12, p≤0.02). Factors associated with increased likelihood of identifying a high-risk site as safe were as follows: flat road profile (adjusted OR=2.00, 95% CI 1.55 to 2.57), intersections (OR=1.96, 95% CI 1.43 to 2.68), irregular road surface (OR=3.56, 95% CI 2.68 to 4.71), nearby road obstacles (OR=2.57, 95% CI 1.96 to 3.39) and visible rain (OR=1.85, 95% CI 1.48 to 2.32). Conclusion The methods used in this study might be useful in prioritising cost-effective improvements at high-risk sites.

Prognostic studies are essential to understand the role of particular prognostic factors and, thus, improve prognosis. In most studies, disease progression trajectories of individual patients may end up with one of mutually exclusive endpoints or can involve a sequence of different events. One challenge in such studies concerns separating the effects of putative prognostic factors on these different endpoints and testing the differences between these effects. In this article, we systematically evaluate and compare, through simulations, the performance of three alternative multivariable regression approaches in analyzing competing risks and multiple-event longitudinal data. The three approaches are: (1) fitting separate event-specific Cox's proportional hazards models; (2) the extension of Cox's model to competing risks proposed by Lunn and McNeil; and (3) Markov multi-state model. The simulation design is based on a prognostic study of cancer progression, and several simulated scenarios help investigate d...

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.

International audience; We did a prospective observational 9-month long study to quantify risk factors of managerial and hygiene practices, and pig-health status for Salmonella seroconversion of fattening pigs reared in subclinically infected French farrow-to-finish farms. During the fattening phase, 2 649 pigs belonging to the same batch of contemporary pigs, from 89 conventional farrow-to-finish farms were individually followed and regularly blood sampled on a monthly basis. Farm recruitment was based on the farmer's willingness to cooperate. Pig status was assessed using an indirect ELISA test. Evolution of the serological status was studied by means of survival analysis. A Cox proportional-hazards model, taking into account the clustering of animals at the farm level, was used to examine the effects of explanatory variables on the time to Salmonella seroconversion of pigs. Applying group level antibiotic treatment to the pigs during the fattening period (Hazard Ratio (HR) = 2.4; 95% CI: 1.7, 3.4) was identified as a risk factor for Salmonella seroconversion, as the presence of residual Salmonella contamination in the fattening pen before placing the pigs into the pens (HR = 1.9; 95% CI: 1.2, 2.9). Porcine reproductive and respiratory syndrome virus (PRRSV) seropositivity during the fattening period also indicated an increased hazard for seroconversion (HR = 1.6; 95% CI: 1.1, 2.5). The batch size was identified as a risk factor for Salmonella seroconversion: the higher the number of pigs was in the fattening room followed, the higher was the risk (HR(+10 pigs) = 1.05 for a 10-pig increment; 95% CI: 1.03, 1.06). The biosecurity measures of wearing specific clothes before entering the facilities (HR = 0.5; 95% CI: 0.3, 0.9) and enclosing the pig farm facilities were protective (HR = 0.4; 95% CI: 0.2, 0.8).

Although several prognostic factors have been identified in ALS, there remains some discordance concerning the prognostic significance of the age and clinical form at onset. In order to clarify these findings, we have analysed already known prognostic factors using a multi-state model. Two hundred and twenty-two sporadic ALS patients were followed. A simple unidirectional three-states model was used to summarize clinical course of ALS. States 1 and 2 reflected the progression of neurological impairment and state 3 represented the end of follow-up (tracheotomy or death). Gender, diagnostic delay, body mass index (BMI) and slow vital capacity (SVC) were also recorded. A time-inhomogeneous Markov model with piecewise constant transition intensities was used to estimate the effect of the covariates in each transition. The bulbar form at onset was only correlated with a more rapid clinical progression between state 1 and state 2. In contrast, an advanced age at diagnosis affected only survival from state 2. This methodological approach suggests that these two factors have a different prognostic significance: age at onset is related to patient's survival and the clinical form at onset predicts the progression of motoneuronal impairment in different regions.

Background Despite the progress in the Prevention of the Mother-to-Child Transmission of HIV (PMTCT), the paediatric HIV epidemic remains worrying in Cameroon. HIV prevalence rate for the population of pregnant women was 7.6 % in 2010 in Cameroon. The extent of the paediatric HIV epidemic is needed to inform policymakers. We developed a stochastic simulation model to estimate the number of new paediatric HIV infections through MTCT based on the observed uptake of services during the different steps of the PMTCT cascade in Cameroon in 2011. Different levels of PMTCT uptake was also assessed. Methods A discrete events computer simulation-based approach with stochastic structure was proposed to generate a cohort of pregnant women followed-up until 6 weeks post-partum, and optionally until complete breastfeeding cessation in both prevalent and incident lactating HIV-infected women. The different parameters of the simulation model were fixed using data sources available from the 2011 national registry surveys, and from external cohorts in Cameroon. Different PMTCT coverages were simulated to assess their impact on MTCT. Available data show a low coverage of PMTCT services in Cameroon in 2011. Results Based on a simulation approach on a population of 995, 533 pregnant women, the overall residual MTCT rate in 2011 was estimated to be 22.1 % (95 % CI: 18.6 %–25.2 %), the 6-week perinatal MTCT rate among prevalent HIV-infected mothers at delivery is estimated at 12.1 % (95 % CI: 8.1 %–15.1 %), with an additional postnatal MTCT rate estimated at 13.3 % (95 % CI: 9.3 %–17.8 %). The MTCT rate among children whose mothers seroconverted during breastfeeding was estimated at 20.8 % (95 % CI: 14.1 %–26.9 %). Overall, we estimated the number of new HIV infections in children in Cameroon to be 10, 403 (95 % CI: 9, 054–13, 345) in 2011. When PMTCT uptake have been fixed at 100 %, 90 % and 80 %, global MTCT rate failed to 0.9 % (95 % CI: 0.5 %–1.7 %), 2.0 % (95 % CI: 0.9 %–3.2 %) and 4.3 % (95 % CI: 2.4 %–6.7 %) respectively. Conclusions This model is helpful to provide MTCT estimates to guide the national HIV policy in Cameroon. Increasing supply and uptake of PMTCT services among prevalent HIV infected pregnant women, as well as HIV-prevention interventions including the offer and acceptance of HIV testing and counselling in lactating women could reduce significantly the residual HIV MTCT in Cameroon. A public health effort should be made to encourage health care workers and pregnant women to use PMTCT services until complete breastfeeding cessation. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1336-2) contains supplementary material, which is available to authorized users.

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.

The paper reviews methodological difficulties that arise when using observational studies to evaluate the effect of prenatal screening and treatment. The principle of each difficulty is described and then illustrated by a clinical example of toxoplasmosis in pregnancy and its consequences. Methods to deal with these difficulties are described. Given the limitations of existing observational studies and lack of randomised controlled trials, a systematic review of cohort studies offers the best approach for exploring potential biases.

Antenatal HIV seroprevalence surveys are important tools to understand the extent of the HIV epidemic in Africa. The main objective is to describe HIV prevalence trends from 1995–2002 in pregnant women consulting antenatal clinics in Abidjan, Côte d'Ivoire. We proposed HIV test to pregnant women consulting antenatal clinics in Abidjan from 1995–2002 in a programme of prevention of mother-to-child transmission of HIV. Yearly prevalence was estimated. Overall, 36,442 women were tested. Prevalence decreased from 14–15% in 1995–96 to 11% in 2002. The prevalence among 18–22-year-old women dropped from 15% in 1995 to 8% in 2002, while for older women it increased slightly, or remained stable from 1995–1999 and decreased thereafter. HIV prevalence among women consulting antenatal clinics has been decreasing overall. This is the first such report among pregnant women in Abidjan, probably the result of different phenomena: ageing of the epidemic and behaviour changes (disease awareness and prevention campaigns).

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.

Objective: To assess the 24 month efficacy of a maternal short-course zidovudine regimen to prevent mother-to-child transmission (MTCT) of HIV-1 in a breastfeeding population in West Africa. Methods: Data were pooled from two clinical trials: DITRAME-ANRS049a conducted in Abidjan Cote dIvoire and Bobo-Dioulasso Burkina-Faso and RETRO-CI conducted in Abidjan. Between September 1995 and February 1998 consenting HIV-1-seropositive women were randomly assigned to receive zidovudine (300 mg) or placebo: one tablet twice daily from 36-38 weeks gestation until delivery then in DITRAME only for 7 more days. Pediatric HIV-1 infection was defined as a positive HIV-1 polymerase chain reaction or if aged > 15 months a positive HIV-1 serology. Cumulative risks (CR) of infection were estimated using a competing risk approach with weaning as a competing event. Results: Among 662 live-born children 641 had at least one HIV-1 test. All but 12 children were breastfed. At 24 months overall CR of MTCT were 0.225 in the zidovudine and 0.302 in the placebo group a 26% significant reduction. Among children born to women with CD4 cell counts 500/ml at enrolment CR of MTCT were similar 0.396 in the zidovudine and 0.413 in the placebo group. Among children born to women with CD4 cell counts > 500/ml CR of MTCT were 0.091 in the zidovudine and 0.220 in the placebo group a significant 59% reduction. Conclusion: A maternal short-course zidovudine regimen reduces MTCT of HIV-1 at age 24 months despite prolonged breastfeeding. However efficacy was observed only among women with CD4 cell counts > 500/ml. New interventions should be considered to prevent MTCT especially for African women with advanced HIV-1 immunodeficiency. (author’s)

OBJECTIVE To study the predictors of virological rebound in patients having early virological response to protease inhibitor (PI)-containing regimen. DESIGN AND METHODS APROCO cohort study prospectively enrolled 1283 HIV-infected patients starting a PI-containing regimen in 1997-1999. Adherence to therapy was measured with self-administered questionnaires after 4 months of therapy (M4). Virological rebound was defined as a viral load (VL) > 500 copies/ml in patients having early virological response, defined as a VL < 500 copies/ml at M4. Predictors of time to virological rebound were studied with multivariate proportional hazards model. RESULTS During a median follow-up of 20 months, virological rebound was observed in 32% of the 830 patients with early virological response. Virological rebound was more frequent when patients had received previous antiretroviral treatment [adjusted hazards ratio (HR) = 2.4; P < 0.0001], were younger (HR = 1.4 per each 10 years younger; P < 0.0001), had baseline CD4 cell count < 500 x 106/l (HR = 2.3; P < 0.001), had higher baseline VL (HR = 1.4 per each log10 copies/ml higher; P < 0.001), reported low adherence to therapy at M4 (HR = 2.1; P < 0.001) or had stopped PI at M4 (HR = 1.7; P = 0.04). CONCLUSION Initiation of treatment at a stage of preserved immunity is associated with a more durable virological response under protease inhibitor. Every effort should be made to monitor and strengthen adherence to therapy, even in patients having early virological response.

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.

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.

Background The perception of abuse might explain why France has not prohibited all forms of corporal punishment; it has potential important implications on uses of corporal punishment, intention to report abuse cases and acceptability of laws or prevention programs. The aim of our study was to compare perception of physical child abuse between professionals and parents in an emergency department and determine which characteristics are associated with this perception. Methods A cross-sectional study was conducted from November 2013 to October 2014 in the emergency department of the Bordeaux paediatric university hospital, France. An anonymous self-questionnaire, including vignettes describing hypothetic situations of potential physical child abuse and items related to socio-demographic and family characteristics, was administered to professionals and parents. Vignettes included varying child’s age, child’s behaviour, frequency of caregiver’s behaviour, hitting with/without an object, and child’s target body part. Respondents were asked to rate the acceptability of situations of eight random vignettes on a 100-mm visual analogic scale. Analyses were multivariate mixed Poisson regressions. Results One thousand and one participants assessed the vignettes. Participants were predominantly female (64%), married or living with a partner (87%), with a median age of 34 years. Professionals significantly assessed vignettes as more acceptable than parents (mean rating multiplied by 2.8; p Conclusions Such differences indicate the need for additional research to better appreciate consequences and severity of physical violence toward children, and the need to educate parents and professionals.

Objective We assessed the effect of HIV status disclosure on retention in care from initiation of antiretroviral therapy (ART) among HIV-infected children aged 10 years or more in Cote d'Ivoire, Mali and Senegal. Methods Multi-centre cohort study within five paediatric clinics participating in the IeDEA West Africa collaboration. HIV-infected patients were included in this study if they met the following inclusion criteria: aged 10-21 years while on ART; having initiated ART ≥ 200 days before the closure date of the clinic database; followed ≥ 15 days from ART initiation in clinics with ≥ 10 adolescents enrolled. Routine follow-up data were merged with those collected through a standardized ad hoc questionnaire on awareness of HIV status. Probability of retention (no death or loss-to-follow-up) was estimated with Kaplan-Meier method. Cox proportional hazard model with date of ART initiation as origin and a delayed entry at date of 10th birthday was used to identify factors associated with death or loss-to-follow-up. Results 650 adolescents were available for this analysis. Characteristics at ART initiation were: median age of 10.4 years; median CD4 count of 224 cells/mm³ (47% with severe immunosuppression), 48% CDC stage C/WHO stage 3/4. The median follow-up on ART after the age of 10 was 23.3 months; 187 adolescents (28.8%) knew their HIV status. The overall probability of retention at 36 months after ART initiation was 74.6% (95% confidence interval [CI]: 70.5-79.0) and was higher for those disclosed compared to those not: adjusted hazard ratio for the risk of being death or loss-to-follow-up = 0.23 (95% CI: 0.13-0.39). Conclusion About 2/3 of HIV-infected adolescents on ART were not aware of their HIV status in these ART clinics in West Africa but disclosed HIV status improved retention in care. The disclosure process should be thus systematically encouraged and organized in adolescent populations.

Background Clinical evolution of HIV-infected children who have not yet initiated antiretroviral treatment (ART) is poorly understood in Africa. We describe severe morbidity and mortality of untreated HIV-infected children. Methods All HIV-infected children enrolled from 2004-2009 in a prospective HIV programme in two health facilities in Abidjan, Côte d'Ivoire, were eligible from their time of inclusion. Risks of severe morbidity (the first clinical event leading to death or hospitalisation) and mortality were documented retrospectively and estimated using cumulative incidence functions. Associations with baseline characteristics were assessed by competing risk regression models between outcomes and antiretroviral initiation. Results 405 children were included at a median age of 4.5 years; at baseline, 66.9% were receiving cotrimoxazole prophylaxis, and 27.7% met the 2006 WHO criteria for immunodeficiency by age. The risk of developing a severe morbid event was 14% (95%CI: 10.7 - 17.8) at 18 months; this risk was lower in children previously exposed to any prevention of mother-to-child-transmission (PMTCT) intervention (adjusted subdistribution hazard ratio [sHR]: 0.16, 95% CI: 0.04 - 0.71) versus those without known exposure. Cumulative mortality reached 5.5% (95%CI: 3.5 - 8.1) at 18 months. Mortality was associated with immunodeficiency (sHR: 6.02, 95% CI: 1.28-28.42). Conclusions Having benefited from early access to care minimizes the severe morbidity risk for children who acquire HIV. Despite the receipt of cotrimoxazole prophylaxis, the risk of severe morbidity and mortality remains high in untreated HIV-infected children. Such evidence adds arguments to promote earlier access to ART in HIV-infected children in Africa and improve care interventions in a context where treatment is still not available to all.

International audience; OBJECTIVE: Endpoints used for the evaluation of immunogenicity in vaccine trials are often the proportion of individuals with immune response or geometric means of antibody concentrations for each serotype. When a vaccine includes several types of the same species, we illustrate how an endpoint combining all responses may improve clinical relevance and statistical power. STUDY DESIGN AND SETTINGS: The motivating example was the ANRS 114 Pneumovac trial where the effect of two vaccine strategies against Streptococcus pneumoniae was assessed in adults infected by the Human Immunodeficiency Virus. The power associated with several endpoints was calculated in the example and in simulations. A new endpoint based on four ordered levels is formulated and analyzed by using a proportional odds model. RESULTS AND CONCLUSION: The analysis of this new endpoint led to an odds ratio allowing detection of improvement and detriment. In the simulation study, this endpoint was associated with the largest statistical power by increasing the amount of information used as compared with usual endpoints. We recommend this new endpoint formulation in the formal development of a new vaccination regimen, whenever applicable.

Objectives Altered angiogenesis is a characteristic feature in SSc and remains ill-understood. VEGF is believed to play a central role. Serum VEGF is elevated in SSc patients but questions remain concerning the source of circulating VEGF. Here we investigated platelet activation and the role of platelets as a source of VEGF and other angiogenic mediators in this disease. Methods A cohort of 40 patients with SSc was included. Age- and sex-matched healthy subjects and subjects presenting a primary RP were included as controls. Platelets were isolated, activated with thrombin and the secretion of VEGF, platelet derived growth factor, homodimeric form BB (PDGF-BB), TGF-beta1 and angiopoietins-1 and -2 measured. Plasma concentrations of these mediators and the functionality of platelet-derived VEGF were also studied. Platelet activation was assayed by measuring plasma beta-thromboglobulin and expression of P-selectin on platelets. The effect of iloprost on VEGF secretion by platelets was studied. Results Platelets from SSc patients, in contrast to controls, secreted large amounts of VEGF when activated, but not PDGF-BB, TGF-beta1 or angiopoietins. Increased expression of membrane P-selectin confirmed platelet activation in the patients. Iloprost inhibited VEGF secretion by platelets both in vivo and in vitro, through inhibition of platelet activation. Conclusions Platelets transport high levels of VEGF in SSc. They may contribute to circulating VEGF because of ongoing activation in the course of the disease. If activated at the contact of injured endothelium, platelets may be important in the altered angiogenesis associated with the disease through the secretion of high levels of VEGF.

Before the introduction of highly active antiretroviral therapy (HAART) in 1996, monitoring the epidemics of HIV infection was extensively based on back-calculating the number of new HIV infections from AIDS surveillance data and knowledge of the AIDS incubation period distribution. However, the increase in the AIDS incubation period induced by HAART has complicated the use of AIDS diagnosis data only, and made it necessary to supplement these data with HIV diagnosis data. We explore the advantage of combining HIV and AIDS surveillance data in the context where the HIV diagnosis data are available only for the most recent years. Extending the earlier work of Aalen et al. (Statist. Med. 1997; 16(19):2191-2210) based on a discrete-time Markov model that describes simultaneously disease progression, HIV diagnosis and treatment intake, we propose a penalized likelihood approach to estimate smooth HIV incidence, together with HIV diagnosis rates. The smoothing parameter is chosen using an approximated cross-validation criterion. In a simulation study, we show that incorporation of HIV test information improves the precision of the estimation of the incidence of infections in recent periods. The method is illustrated using HIV and AIDS surveillance data collected by the Institut de Veille Sanitaire, France.

International audience; The incidence and determinants of severe morbidity recurrence in sub-Saharan African HIV-infected adults on antiretroviral therapy (ART) have never been reported. In a prospective cohort study of HIV-infected adults in Abidjan the association of severe morbidity occurrence and recurrence with follow-up CD4 counts and ART on/off status was analyzed by means of multivariate failure analysis for recurrent events (Prentice, Williams, and Peterson model). A total of 608 patients (median CD4 290/mm3 ) was followed off ART for 1824 person-years (PY). Of these 187 started HAART (median CD4 174/mm3 ) and were followed for 328 PY. The incidence of first, second, and third severe morbidity events was 40.6/100 PY, 68.4/100 PY, and 93.9/100 PY during the off-ART period, and 28.4/100 PY, 39.4/100 PY, and 37.6/100 PY during the on-ART period, respectively. The rates of recurrences were higher than the rates of first episodes for almost all diseases, even after stratifying by CD4 count and by ART on/off status. In multivariate analysis, the time-updated CD4 count was independently associated with increasing rates of morbidity first events and recurrences, after adjustment on other covariates (p > 10(4) ). By contrast, there was no association between the ART on/off status and the morbidity rates after adjustment for CD4 count (p = 0.37). Introducing ART led to a clear reduction in morbidity, mainly related to the ART-induced increase in CD4 count. In HIV-infected patients on ART, the incidence of severe morbidity varied with the past history of morbidity. The past history of morbidity should be taken into account when comparing HIV morbidity rates before and after ART initiation.

International audience; The objective of this study was to assess the performance of 4 biologic tests designed to detect recent HIV-1 infections in estimating incidence in West Africa (BED, Vironostika, Avidity, and IDE-V3). These tests were assessed on a panel of 135 samples from 79 HIV-1-positive regular blood donors from Abidjan, C?d'Ivoire, whose date of seroconversion was known (Agence Nationale de Recherches sur le SIDA et les H?tites Virales 1220 cohort). The 135 samples included 26 from recently infected patients (< or =180 days), 94 from AIDS-free subjects with long-standing infection (>180 days), and 15 from patients with clinical AIDS. The performance of each assay in estimating HIV incidence was assessed through simulations. The modified commercial assays gave the best results for sensitivity (100% for both), and the IDE-V3 technique gave the best result for specificity (96.3%). In a context like Abidjan, with a 10% HIV-1 prevalence associated with a 1% annual incidence, the estimated test-specific annual incidence rates would be 1.2% (IDE-V3), 5.5% (Vironostika), 6.2% (BED), and 11.2% (Avidity). Most of the specimens falsely classified as incident cases were from patients infected for >180 days but

To study the factors associated with progression, recovery and death from different grades of disability in elderly people.The sample included 3198 participants of the PAQUID ('Personnes Agées QUID') cohort, aged 65 and over and community-dwellers at baseline. Subjects were re-interviewed 1, 3, 5, 8 and 10 years after baseline. A five-state Markov model was used to estimate transition intensities between four grades of disability and toward death. We used a hierarchic scale of disability, which combines basic and instrumental activities of daily living and mobility. Several explanatory variables were investigated: medical, personal and environmental factors.The factors associated with progression and/or no recovery of disability were cardiovascular diseases, stroke and diabetes, low cognition, visual impairment and dyspnoea (for pathologies and impairments), older age, female gender, low educational level (for risk factors), depression (for intra-individual factor) and being married, recent hospitalization and number of drugs (for extra-individual factors). Older age, male gender, tobacco consumption and living in an urban area were associated with mortality.These findings confirm the independent contribution of each group of variables in the disablement process and stress their different impact on progression of disability or on recovery from different grades of disability.

From 1996 to 1998, a phase III, placebo-controlled, therapeutic trial was conducted in Abidjan, Ivory Coast, to assess the efficacy of cotrimoxazole prophylaxis in reducing severe morbidity in adults at early stages of human immunodeficiency virus infection. The authors used the real data from this trial to simulate three Bayesian interim analyses. Three prior distributions were considered: a noninformative one, a skeptical one, and one based on external information. The posterior distribution was calculated by using directed acyclic graphs and Gibbs sampling. This Bayesian approach showed different results according to the prior distribution chosen. Although use of the noninformative prior would have led to stopping the trial at the same time that the frequentist approach would have, the skeptical prior would have led to continuing it, and the prior based on external data would have led to stopping it 1 year earlier.

The objective of this study was to examine the impact of dementia on disability progression and mortality, and to analyze the modifying effect of risk factors and extra-individual factors. A sample of 3,403 participants in the PAQUID study was followed for 10 years. Disability was assessed on a 4-grade scale: no disability, disabled only on the Rosow-Breslau scale, disabled on the Rosow-Breslau scale and on instrumental activities of daily living (IADL) scales, and disabled on the Rosow-Breslau, IADL and activities of daily living (ADL) scales. A Markov model was used to estimate the effect of explanatory variables on disability and mortality. Controlling for age, gender, education, place of residence, medical care and informal support, dementia had a strong significant effect on progression to IADL and then to ADL disability. Dementia did not increase the risk of death, once disability was taken into account, except from the lowest disability grade.

International audience; The aim of this study was to evaluate the impact of the pre-slaughter process on Salmonella caecal contamination of pigs at slaughter. An observational study was carried out in 2001 on 101 conventional farrow-to-finish pig farms. On each farm, one batch of contemporary pigs was followed from the end of the fattening period until slaughter. The Salmonella bacteriological status of the batches was assessed by environmental samples of faecal material. The serological Salmonella status was obtained on 30 individually identified market-age pigs using an indirect ELISA test. At the slaughterhouse, 25 g of caecal contents were taken from 10 of the identified pigs. Faecal and caecal material were analysed according to a classical bacteriological method. A questionnaire was designed to obtain information about the type of feeding during the fattening period (dry versus wet), the duration of fasting on the farm before leaving for the slaughterhouse, the duration of transport between the farm and the slaughterhouse, the holding time in lairage at the slaughterhouse and loading and unloading conditions on the farm and at the slaughterhouse. To assess the relationships between these factors and the Salmonella caecal status of the pigs and the batches, two logistic models were fitted at the individual and at the batch level, respectively. The first analysis was performed using a random effects logistic regression model. The second analysis was based on a cumulative logit model with a positive caecal rate classified into three classes as the outcome variable. The results showed that the Salmonella status of market-age pigs assessed on the farm either by serological or bacteriological examinations and the time spent in lairage before slaughtering played a crucial role on caecal contamination. In the light of these results, actions should be considered both on the farm and at the slaughterhouse to decrease the risk of Salmonella contamination of the caecal contents.

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 Cote 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.

To assess the postnatal transmission (PT) risk of HIV-1 after a maternal short-course zidovudine regimen in a breastfeeding population.Data were pooled from two trials: ANRS 049a DITRAME (Abidjan, Côte d'Ivoire and Bobo-Dioulasso, Burkina-Faso) and RETROCI (Abidjan). Consenting HIV-1 seropositive women were randomized at 36-38 weeks' gestation between September 1995 and February 1998, to receive oral zidovudine or placebo: one tablet twice daily until delivery, and in DITRAME only, for 7 more days. A PT case was infection in a child with a negative HIV-1 PCR at age/= 30 days who later became infected as defined by a positive HIV-1 PCR, or if aged/= 15 months, a positive HIV serology. Cumulative risks (CR) of PT were computed using a competing risk approach with weaning as a competing event.At age 24 months, CR for PT were similar in the zidovudine (9.8%, n = 254) and placebo groups (9.1%, n = 225). In a multivariate model of PT risk factors, the treatment effect was not significant, maternal CD4 cell count500 x 10(6)/l at entry tripled the hazard compared to women with CD4 cell counts/= 500 x 10(6)/l [hazard ratio (HR), 3.14; 95% confidence interval (CI), 1.31-7.49] as well as an increased maternal plasma viral load at entry (HR, 2.65 for 1 log(10) increase; CI, 1.75-4.00).PT occurred at a similar rate between arms and therefore reduced the long-term overall efficacy of this peripartum zidovudine regimen at age 24 months. The higher risk of PT among women with low CD4 cell count emphasizes the importance of identifying interventions to prevent PT for these women.

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 percent. 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. (authors)

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.

International audience; 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.

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.