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.

Analysis of the effect of aluminum in drinking water and transferrin C2 allele on Alzheimer's disease.

Although highly controversial, the hypothesis of a link between aluminum (Al) in drinking water and Alzheimer's disease (AD) has been supported by several epidemiological studies. Transferrin (Tf) is a major transport protein for both iron and Al. Moreover, it has been demonstrated that defective binding of iron and Al to the Tf variant C2 could be present in AD. Individuals carrying the Tf C2 allele might therefore be at greater risk of developing AD. We investigated whether the Tf C2 allele might be responsible for susceptibility to AD in a sample of 292 subjects (with 55 AD) aged > or = 75 years from south-west France, some exposed to high levels of Al in tap water (n = 181 subjects) and others to low levels of Al (n = 111 subjects). We also examined the combined genetic effects of Tf C2 and epsilon4 allele of apolipoprotein E gene (ApoE). Logistic regression analysis showed that neither Tf C2 nor its interaction with Al or with the epsilon4 allele of the ApoE were significantly associated with the risk of AD.

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.

Evaluation and simplification of the World Health Organization clinical case definition for paediatric AIDS.

The World Health Organization (WHO) clinical case definition for paediatric AIDS was tested during a 1-month period on 221 consecutive hospitalized children in Kigali, Rwanda. Relevant clinical features not included in the WHO case definition were also evaluated. Thirty-four out of the 221 children (15.4%) were HIV seropositive. Although the specificity of the WHO case definition was high (92%), the sensitivity and the positive predictive value (PPV) were low (41 and 48%, respectively). The following individual signs had a PPV at least equal to the complete WHO case definition: chronic diarrhoea (47%), respiratory distress secondary to lower respiratory tract infection (50%), oral candidiasis (53%), parotitis (67%), generalized lymphadenopathy (88%), and herpes zoster infection (100%). When logistic regression analysis was done on the nine variables included in the WHO case definition, confirmed maternal infection was the best predictive variable for HIV seropositivity in children (P less than 10(-5). We further excluded the serological status of the mother from the analysis and performed a stepwise logistic regression analysis on the 18 clinical signs and symptoms for which information had been collected. Those signs and symptoms contributing the most to the regression were: respiratory distress, chronic diarrhoea and generalized lymphadenopathy. Based on these findings, we propose a simplified clinical case definition for paediatric AIDS in Africa with better sensitivity, specificity and PPV than the WHO case definition. Further work is needed using this approach to develop case definitions useful for epidemiological surveillance and for case management.

PIP: The World Health Organization (WHO) clinical case definition for pediatric acquired immunodeficiency syndrome (AIDS) was evaluated over a 1-month period in 221 consecutive hospitalized children in Kigali, Rwanda. The median age of the children studied was 18 months (range, 1 month-14 years); 55% were boys. 34 (15%) of these 221 children were seropositive for the human immunodeficiency virus (HIV). Although the specificity of the WHO case definition was high (92%), its sensitivity was only 41% and the positive predictive value was 48%. The following individual signs had a positive predictive value at least equal to the complete WHO case definition: chronic diarrhea (47%), respiratory distress secondary to lower respiratory tract infection (50%), oral candidiasis (53%), parotitis (67%), generalized lymphadenopathy (88%), and herpes zoster infection (100%). Logistic regression analysis on the 9 variables included in the WHO case definition indicated that confirmed maternal HIV infection was the best predictive variable for HIV seropositivity in children. When maternal serological status (rarely available in Rwanda) was excluded from the analysis and a stepwise logistic regression analysis was performed on the 18 clinical signs and symptoms for which data had been collected, respiratory distress, chronic diarrhea, and generalized lymphadenopathy emerged as the signs contributing the most. On the basis of these findings, a simplified clinical case definition of pediatric AIDS is proposed for settings where resources are limited and HIV seroprevalence is high. According to this definition, pediatric AIDS should be suspected in a child presenting with 1 or both of the following clinical signs: respiratory distress secondary to lower respiratory tract infection and/or generalized lymphadenopathy. However, it is necessary to test this definition on a larger scale in Central Africa and in other parts of the world with different rates of HIV seroprevalence.

Occupation during life and memory performance in nondemented French elderly community residents.

Using data obtained during the baseline screening of the PAQUID cohort, an epidemiologic study on brain aging conducted in the Bordeaux area of France, we studied the relationship between lifetime occupation and memory performance in visual recognition (Benton Visual Retention Test; BVRT) and verbal induced recall (Wechsler Paired Associates Test; WPAT) in 2,720 elderly community residents. Occupational category was strongly correlated with poor memory performance for both the BVRT and the WPAT. Independent of the educational level, the risk of having poor memory performance was two to three times greater for farmers, domestic service employees, and blue-collar workers than for professionals/managerials. Occupational category should be taken into account in future cross-national studies on brain aging.

Marital status and risk of Alzheimer's disease: a French population-based cohort study.

OBJECTIVE: To analyze the relationship between marital status and risk of AD or dementia. METHODS: This study was carried out from the Personnes Agées QUID (PAQUID) cohort, an epidemiologic study on normal and pathologic aging after age 65 years. The PAQUID cohort began in 1988. Individuals were followed up at 1, 3, and 5 years, with an active detection of dementia. Marital status was divided into four categories: widowed, never married, divorced or separated, and the reference category, married or cohabitant. The longitudinal relationship between marital status and risk of incident AD or dementia was analyzed by a Cox model with delayed entry. RESULTS: Among the 3,675 individuals initially not demented, 2,106 were married or cohabitants, 1,287 were widowers, 179 were never married, and 103 were divorced or separated. Among the 2,881 individuals reevaluated at least once for the risk of dementia during the 5-year follow-up, 190 incident cases of dementia were identified, including 140 with AD. The relative risks (RRs) of dementia (RR = 1.91, p = 0.018) and of AD (RR = 2.68, p<0.001) were increased for the never-married individuals compared with those who were married or cohabitants. This excess of risk was specifically associated with AD. Adjustment for other risk factors of dementia (education, wine consumption), or for factors reflecting social environment, leisure activities, and depression, did not modify the risk of AD for never-married individuals (RR = 2.31, p = 0.02). CONCLUSIONS: We confirmed an association between marital status and AD, with an excess risk observed among never-married individuals. This association may provide clues about the pathogenesis of AD.

Tobacco consumption and cognitive impairment in elderly people. A population-based study.

We examined the relationship between tobacco consumption and Alzheimer's disease (AD), cognitive deficit, and memory performances in elderly community residents of southwestern France. Subjects were considered to have a cognitive deficit if they scored under 24 on the French version of the Mini-Mental State Examination, and poor memory performances if they scored under 8 on the Benton Visual Retention Test. Among the 3770 subjects who gave information about their smoking habits, only 356 (9.5%) were current smokers, 998 (26.5%) were past smokers, and 2416 (64%) were never smokers. Current smokers (odds ratio (OR) = 0.52, P < 0.001) and past smokers (OR = 0.54, P < 0.001) had a lower risk of cognitive deficit than did never smokers. However, this significant relationship disappeared after adjustment for potential confounding factors such as occupational category (OR = 0.91 (not significant) for current smokers and OR = 0.87 (not significant) for past smokers). Similar results were obtained for the risk of AD and of poor memory performances. The apparent protective effect of smoking habits on cognitive abilities could be due to a confounding effect of occupational category.

A cognitive screening battery for dementia in the elderly.

The objective of this study is to propose a screening instrument for dementia based on a reduced number of neuropsychological tests. The sample consists in the pooled data of the five follow-up visits of the Paquid cohort study on cerebral aging: the estimation sample included 2792 subjects (8830 observations) and the validation sample included 985 subjects (2643 observations). Among scores significantly associated with dementia, we retained only those that increased the specificity of the model for a sensitivity of one. Seven neuropsychological tests and the MMSE subscores were considered. The most discriminant combination of tests included the MMSE and the subscores "orientation to time" and "recall three objects," the Benton Visual Retention Test, and Isaacs' Set Test of verbal fluency. The specificity of this screening instrument was 0. 77 for a sensitivity of 1.

Incidence of dementia and Alzheimer's disease in elderly community residents of south-western France.

BACKGROUND: Dementia is a growing problem in developed countries. The aim of this paper is to estimate incidence rates of dementia, Alzheimer's disease and vascular dementia in a community population of South-Western France. METHODS: A sample of 2792 subjects was selected and followed-up 1 year and 3 after the initial screening. At each visit, a standardized questionnaire was administered by trained psychologists. Demented subjects were identified using a two-step procedure. The first step consisted of a systematic screening by the psychologist using DSM IIIR criteria for dementia. In the second step, subjects who fulfilled the DSM IIIR criteria were examined by a neurologist. NINCDS-ADRDA criteria were applied to diagnose Alzheimer's disease. RESULTS: Incidences of dementia and Alzheimer's disease were estimated at 16.3 and 11.4 per 1000 per year, respectively. Incidence estimates increased with age from 2 per 1000 in subjects aged 65-69 years to 74 per 1000 in subjects > 90 years. Incidence estimates of Alzheimer's disease showed the same increased from 0.7 per 1000 to 66 per 1000. Incidences of dementia and of Alzheimer's disease did not level off with age and were not different between genders.

Loss of maternal measles antibody during infancy in an African city.

Measles epidemics with 20% of the cases under nine months of age continue to occur in Brazzaville, Congo, even though measles vaccination coverage was 77% in the 12- to 23-month age group in 1986. In order to estimate the duration of passive immunity against measles, we conducted a serologic survey of infants aged 2 to 9 months. Measles antibody was measured from capillary blood with the plaque inhibition test. An antibody titre of 40 milli-International Reference Units per ml of serum (mIRU/ml) or less was defined as seronegative. Among the 252 infants studied, the proportion with detectable antibody dropped from 95.8% at 2 months of age to 48.5% at 4 months of age, and to 8.2% in the 7-8 month age group. A simple logistic model with age as the only variable provided an excellent fit to the observed values. Between the ages of 8 and 28 weeks, there was an almost steady decline of approximately 4.7% per week in the proportion of infants who were seropositive. These findings suggest that loss of maternal measles antibody during infancy might be faster than reported in other African populations. Giving measles vaccine to infants before the age of nine months currently recommended by the Expanded Programme on Immunization may be useful in some populations. Further studies of seroconversion and impact on measles are needed.

Instrumental activities of daily living as a screening tool for cognitive impairment and dementia in elderly community dwellers.

OBJECTIVE: To identify which Instrumental Activities of Daily Living (IADL) are related to cognitive impairment, independent of age, sex, and education; to assess the performance of an IADL score using these items in screening for cognitive impairment and dementia in elderly community dwellers. DESIGN: Survey based on the baseline interview of the PAQUID study on functional and cerebral aging. SETTING: Community survey in 37 randomly selected parishes in Gironde, France. SUBJECTS: Random sample of 2,792 community dwellers aged 65 and over (participation rate: 69%). MEASUREMENTS: Two-phase screening: (1) functional assessment, Mini-Mental State Examination (MMSE) and DSM-III criteria for dementia; (2) in DSM-III-positive patients, NINCDS-ADRDA criteria applied by a neurologist. Functional assessment: IADL scale of Lawton and Brody. Criterion standards: cognitive impairment: MMSE score lower than 24; dementia: DSM-III and NINCDS-ADRDA criteria. RESULTS: Four IADL items are correlated with cognitive impairment independent of age, sex, and education: telephone use, use of means of transportation, responsibility for medication intake, and handling finances. A score adding the number of IADL dependencies has a sensitivity of 0.62 and a specificity of 0.80 at the lowest cut-off point (score > 0) for the diagnosis of cognitive impairment. The same score at the same cut-off has a sensitivity of 0.94 and a specificity of 0.71 for the diagnosis of dementia. The prevalence of dementia (2.4%) is reduced by a factor of 12 in subjects independent for the four IADL. CONCLUSION: The four IADL score could be incorporated into the screening procedure for dementia in elderly community dwellers.

Social and leisure activities and risk of dementia: a prospective longitudinal study.

OBJECTIVE: To study the relationship between social and leisure activities and risk of subsequent dementia in older community residents. SETTING: A cohort study of people aged 65 and older were followed-up 1 and 3 years after a baseline screening (the Paquid study). PARTICIPANTS: 2040 older subjects living at home in Gironde (France) were randomly selected and followed for at least 3 years. DATA COLLECTION: Information about social and leisure activities was collected during the baseline screening with an interview by a psychologist. Incident cases of dementia were detected during the first and third year follow-up screenings according to the DSM-III-R criteria. MAIN RESULTS: All but one of the social and leisure activities noted were significantly associated with a lower risk of dementia. Only golden club participation was not significantly associated with this risk. After adjustment for age and cognitive performance measured by the Mini-Mental State Exam, visual memory test, and verbal fluency test, only traveling (Relative risk (RR) = .48,95% Confidence Interval (95% CI) = .24-.94), odd jobs or knitting (RR = .46,95% CI = .26-.85), and gardening (RR = .53, 95% CI = .28-.99) remained significant. CONCLUSIONS: Regular participation in social or leisure activities such as traveling, odd jobs, knitting, or gardening were associated with a lower risk of subsequent dementia.

Evidence for an age-dependent pyrogenic threshold of Plasmodium falciparum parasitemia in highly endemic populations.

The high prevalence of asymptomatic malaria infections and the nonspecific signs and symptoms of the disease make the individual diagnosis of clinical malaria uncertain in highly endemic areas. Longitudinal data obtained during a four-month period from a daily survey of 200 permanent inhabitants (one month-83 years old) living in a holoendemic area were analyzed in a random-effects logistic regression model to investigate the relationship between the level of Plasmodium falciparum parasitemia and risk of fever. It was not possible to build a model that described/summarized correctly this relationship by a continuous function. Findings provide evidence for an age-dependent threshold effect of parasitemia on the occurrence of fever. The level of this threshold varied by 2.45 trophozoites per leukocyte, maximum at one year of age, to 0.5 trophozoites per leukocyte, minimum at 60 years of age. When the parasite density of a person crossed the threshold level corresponding to his or her age, the individual's risk of fever was multiplied by 44 (95% confidence interval = 13.6-144.8). The existence of this threshold effect allows parasite density to be used to distinguish malaria attacks from other causes of fever within an individual and should facilitate the accurate evaluation of the incidence of clinical malaria in highly endemic areas.

The formulae-relating slopes, correlation coefficients and variance ratios used to determine stimulus- or movement-related neuronal activity.

When recording single neuron discharge in an animal during the performance of a conditioned task, the functional interpretation of any change in neuronal activity after the conditioned stimulus but before the conditioned task is difficult. So far, such changes have been described as either stimulus- or movement-related. One way of classifying these two types of response has been to use the slope and correlation coefficient between the response latency and the behavioural reaction time. We show that this method is poor and propose a more valid approach.

A statistical method for the estimation of neuronal response latency and its functional interpretation.

The functional role of many central nervous structures has been inferred from the temporal relationship of a neuronal response with the different sensory and motor events in an experimental design such as when an animal performs a trained movement in response to a conditioned stimulus. However, this kind of data analysis leads to problems in estimating the occurrence and latency of any neuronal response. We examine these problems and propose a novel technique of data analysis to estimate the point of change in a sequence of neuronal discharge. Furthermore, data can be tested to see whether the neuronal response is related to the conditioned stimulus or the motor act. The method can also be used in the simple situation of determining the latency of a neuronal response after a stimulus.

Inference for multi-state models from interval-censored data.

Clinical statuses of subjects are often observed at a finite number of visits. This leads to interval-censored observations of times of transition from one state to another. The likelihood can still easily be written in terms of both transition probabilities and transition intensities. In homogeneous Markov models, transition probabilities can be expressed simply in terms of transition intensities, but this is not the case in more general multi-state models. In addition, inference in homogeneous Markov models is easy because these are parametric models. Non-parametric approaches to non-homogeneous Markov models may follow two paths: one is the completely non-parametric approach and can be seen as a generalisation of the Turnbull approach; the other implies a restriction to smooth intensities models. In particular, the penalized likelihood method has been applied to this problem. This paper gives a review of these topics.

Cerebral and functional aging: first results on prevalence and incidence of the Paquid cohort.

Paquid is an interdisciplinary study designed to investigate cerebral and functional aging. A cohort of 3,777 community residents living in two administrative areas of South-Western France was selected. A standardized questionnaire was administered at home by trained psychologists. The same procedure was applied one and three years after the baseline data collection. The identification of demented subjects was made with a two-step procedure. The first step is a systematic screening by the psychologists using the DSM-III criteria for dementia. Subjects who fulfilled the DSM-III criteria were examined by a neurologist. Diagnosis of dementia is confirmed according to the NINCDS-ADRDA criteria. The Paquid cohort is complemented by a random sample of 357 institutionalized subjects. First results of prevalence and incidence rates show an exponential increase of dementia with age.

A strategy for analysing multiple risk factors with application to cervical pain syndrome.

When studying the possible effects of several factors in a given disease, two major problems arise: (1) confounding, and (2) multiplicity of tests. Frequently, in order to cope with the problem of confounding factors, models with multiple explanatory variables are used. However, the correlation structure of the variables may be such that the corresponding tests have low power: in its extreme form this situation is coined by the term "multicollinearity". As the problem of multiplicity is still relevant in these models, the interpretation of results is, in most cases, very hazardous. We propose a strategy--based on a tree structure of the variables--which provides a guide to the interpretation and controls the risk of erroneously rejecting null hypotheses. The strategy was applied to a study of cervical pain syndrome involving 990 subjects and 17 variables. Age, sex, head trauma, posture at work and psychological status were all found to be important risk factors.

[Influence of histological type on the kinetics of tumor growth and cellular proliferation in autochtonous tumors of mice]. / Influence du caractère histologique sur la cinétique de croissance tumorale et de prolifération cellulaire de tumeurs autochtones chez la souris.

The influence of the tumoral histological characters upon growth kinetics and cellular proliferation parameters was studied for autochtonous chemo-induced tumors in mice. In our experimental conditions, the initial minimum volume from which epithelial tumors on one hand and connective tumors on the other hand are observed and then follow a Gompertzian law, was defined. The change of the histological characters of malignancy was observed during the tumoral growth. Intermitotic delays, durations of the cell cycle phases, growth fraction and degree of cell loss were calculated for epithelial and connective tumors.

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.