Re: aluminum in drinking water and cognitive decline in elderly subjects: the Paquid cohort.
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Biomedical subjects
D Commenges
Publications and source records attributed to D Commenges.
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.
Child↗
Relation between aluminum concentrations in drinking water and Alzheimer's disease: an 8-year follow-up study.
To investigate the effect of aluminum and silica in drinking water on the risk of dementia and Alzheimer's disease, the authors analyzed data from a large prospective cohort (Paquid), including 3,777 subjects aged 65 years and over living at home in 75 civil parishes in Gironde and Dordogne in southwestern France in 1988-1989. The subjects were followed for up for 8 years with an active search for incident cases of dementia or Alzheimer's disease. Mean exposure to aluminum and silica in drinking water was estimated in each area. The sample studied included 2,698 nondemented subjects at baseline, for whom components of drinking water and covariates were available. A total of 253 incident cases of dementia (with 17 exposed to high levels of aluminum), including 182 Alzheimer's disease (with 13 exposed to high aluminum levels), were identified. The relative risk of dementia adjusted for age, gender, educational level, place of residence, and wine consumption was 1.99 (95 percent CI: 1.20, 3.28) for subjects exposed to an aluminum concentration greater than 0.1 mg/liter. This result was confirmed for Alzheimer's disease (adjusted relative risk = 2.14, 95 percent CI: 1.21, 3.80). However, no dose-response relation was found. Inversely, the adjusted relative risk of dementia for subjects exposed to silica (> or = 11.25 mg/liter) was 0.74 (95 percent CI: 0.58, 0.96). These findings support the hypothesis that a high concentration of aluminum in drinking water may be a risk factor for Alzheimer's disease.
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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.
Activities of Daily Living↗
Intake of flavonoids and risk of dementia.
It has been postulated that oxidative stress may play a key role in dementia. This is substantiated by the recent discovery of the protective effect of wine. In wine, the flavonoids--powerful antioxidant substances also contained in tea, fruits and vegetables--have been thought to offer such protection. We investigated whether flavonoid intake could be associated with a lower incidence of dementia in a cohort of 1367 subjects above 65 years of age (Paquid). A questionnaire was used to evaluate their intake of flavonoids and subjects were followed-up for 5 years between 1991 and 1996: 66 incident cases of dementia were observed. We estimated the relative risk (RR) of dementia according to tertiles of flavonoid intake using a Cox model. The age-adjusted RR of dementia was 0.55 for the two highest tertiles compared to the lowest (95% CI: 0.34-0.90; p = 0.02). After additional adjustment for gender, education, weight and vitamin C intake, the RR was 0.49 (95% CI: 0.26-0.92; p = 0.04). We conclude that the intake of antioxidant flavonoids is inversely related to the risk of incident dementia.
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Standardized martingale residuals applied to grouped left truncated observations of dementia cases.
The use of martingale residuals have been proposed for model checking and also to get a non-parametric estimate of the effect of an explanatory variable. We apply this approach to an epidemiological problem which presents two characteristics: the data are left truncated due to delayed entry in the cohort; the data are grouped into geographical units (parishes). This grouping suggests a natural way of smoothing the graph of residuals which is to compute the sum of the residuals for each parish. It is also natural to present a graph with standardized residuals. We derive the variances of the estimated residuals for left truncated data which allows computing the standardized residuals. This method is applied to the study of dementia in a cohort of old people, and to the possible effect of the concentration of aluminum and silica in drinking water on the risk of developing dementia.
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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.
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Multipoint linkage analysis using the weighted-pairwise correlation statistic.
The weighted pairwise correlation (WPC) approach provides simple and flexible non-parametric tests for genetic linkage which may be adapted to qualitative, quantitative or age-dependent traits. Although this statistic has often been used with identity-by-state (IBS) information, there is much to gain by using multipoint identity-by-descent (IBD) information. The purpose of this paper is to use the unified multipoint approach of Kruglyak et al. [1996] with the WPC statistic. We used the simulated data of a complex disease proposed in GAW11 (problem 2) to validate this approach and to compare the multipoint WPC to the IBS-WPC and to the multilocus approach using the conventional non-parametric statistics S(pairs) and S(all). The results suggest that the multipoint WPC may be the most powerful approach.
Genetic Linkage↗
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.
Age Factors↗
Multi-state models in epidemiology.
I first discuss the main assumptions which can be made for multi-state models: the time-homogeneity and semi-Markov assumptions, the problem of choice of the time scale, the assumption of homogeneity of the population and also assumptions about the way the observations are incomplete, leading to truncation and censoring. The influence of covariates and different durations and time-dependent variables are synthesized using explanatory processes, and a general additive model for transition intensities presented. Different inference approaches, including penalized likelihood, are considered. Finally three examples of application in epidemiology are presented and some references to other works are given.
Computer Simulation↗
A penalized likelihood approach for a progressive three-state model with censored and truncated data: application to AIDS.
We consider the estimation of the intensity and survival functions for a continuous time progressive three-state semi-Markov model with intermittently observed data. The estimator of the intensity function is defined nonparametrically as the maximum of a penalized likelihood. We thus obtain smooth estimates of the intensity and survival functions. This approach can accommodate complex observation schemes such as truncation and interval censoring. The method is illustrated with a study of hemophiliacs infected by HIV. The intensity functions and the cumulative distribution functions for the time to infection and for the time to AIDS are estimated. Covariates can easily be incorporated into the model.
Acquired Immunodeficiency Syndrome↗
Are sex and educational level independent predictors of dementia and Alzheimer's disease? Incidence data from the PAQUID project.
OBJECTIVES: To examine the age specific risk of Alzheimer's disease according to sex, and to explore the role of education in a cohort of elderly community residents aged 65 years and older. METHODS: A community based cohort of elderly people was studied longitudinally for 5 years for the development of dementia. Dementia diagnoses were made according to the DSM III R criteria and Alzheimer's disease was assessed using the NINCDS-ADRDA criteria. Among the 3675 non-demented subjects initially included in the cohort, 2881 participated in the follow up. Hazard ratios of dementia were estimated using a Cox model with delayed entry in which the time scale is the age of the subjects. RESULTS: During the 5 year follow up, 190 incident cases of dementia, including 140 cases of Alzheimer's disease were identified. The incidence rates of Alzheimer's disease were 0.8/100 person-years in men and 1.4/100 person-years in women. However, the incidence was higher in men than in women before the age of 80 and higher in women than in men after this age. A significant interaction between sex and age was found. The hazard ratio of Alzheimer's disease in women compared with men was estimated to be 0.8 at 75 years and 1.7 at 85 years. The risks of dementia and Alzheimer's disease were associated with a lower educational attainment (hazard ratio=1.8, p<0.001). The increased risk of Alzheimer's disease in women was not changed after adjustment for education. CONCLUSION: Women have a higher risk of developing dementia after the age of 80 than men. Low educational attainment is associated with a higher risk of Alzheimer's disease. However, the increased risk in women is not explained by a lower educational level.
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[Analysis of longitudinal Gaussian data with missing data on the response variable].
BACKGROUND: Using an application and a simulation study we show the bias induced by missing data in the outcome in longitudinal studies and discuss suitable statistical methods according to the type of missing responses when the variable under study is gaussian. METHOD: The model used for the analysis of gaussian longitudinal data is the mixed effects linear model. When the probability of response does not depend on the missing values of the outcome and on the parameters of the linear model, missing data are ignorable, and parameters of the mixed effects linear model may be estimated by the maximum likelihood method with classical softwares. When the missing data are non ignorable, several methods have been proposed. We describe the method proposed by Diggle and Kenward (1994) (DK method) for which a software is available. This model consists in the combination of a linear mixed effects model for the outcome variable and a logistic model for the probability of response which depends on the outcome variable. RESULTS: A simulation study shows the efficacy of this method and its limits when the data are not normal. In this case, estimators obtained by the DK approach may be more biased than estimators obtained under the hypothesis of ignorable missing data even if the data are non ignorable. Data of the Paquid cohort about the evolution of the scores to a neuropsychological test among elderly subjects show the bias of a naive analysis using all available data. Although missing responses are not ignorable in this study, estimates of the linear mixed effects model are not very different using the DK approach and the hypothesis of ignorable missing data. CONCLUSION: Statistical methods for longitudinal data including non ignorable missing responses are sensitive to hypotheses difficult to verify. Thus, it will be better in practical applications to perform an analysis under the hypothesis of ignorable missing responses and compare the results obtained with several approaches for non ignorable missing data. However, such a strategy requires development of new softwares.
Data Interpretation, Statistical↗
[Analysis of a multicenter clinical trial on pressure ulcer development by a marginal approach in the Cox model].
BACKGROUND: We exemplify the use of a marginal approach with proportional hazards model when failure times are correlated. METHODS: The marginal distribution for each failure time is formulated by the Cox proportional hazards model, while the dependence structure is unspecified. However, a correct variance-covariance estimate of the regression coefficients that takes into account the intra-group correlation is proposed. The program MULCOX2 which implements this statistical methodology is used to assess the effect of a nutritional supplementation intervention on pressure ulcer development on critically ill older patients from a multicentric trial (involving 19 wards). We compare the results obtained with those of the usual Cox regression. RESULTS: The naive approach yields much smaller standard error estimates of the regression parameters than the robust approach. CONCLUSION: In our example, the results obtained with the marginal approach do not modify the conclusions: a nutritional supplementation intervention tends to decrease significantly the formation of pressure ulcers. However in other situations, ignoring the intra-cluster dependence could lead to invalid statistical inference. The variability of the estimated effects by MULCOX2 can be quite sensitive to the number of clusters in the sample and to the clusters size.
Humans↗
[Competitive risks and multi-state models in epidemiology].
An introduction to multi-state models is presented. Survival models can be considered as simple multi-state models; models with competing risks allow to consider several mortality causes: they enable estimating cause-specific mortality rates; however, care must be exerted for the interpretation of survival functions in such models. The illness-death model is very useful for the study of chronic diseases. Transition intensities can be estimated using conventional Cox models when observations are done in continuous time. In that model too, one must avoid pitfalls when interpreting survival functions.
Epidemiologic Methods↗
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.
Age Factors↗
Illustration of analysis taking into account complex survey considerations: the association between wine consumption and dementia in the PAQUID study. Personnes Ages Quid.
Epidemiologists are increasingly looking to large-scale sample surveys to provide data for studies of the associations between known or suspected risk factors and disease. More often than not, widely available statistical software packages have been used to analyze such data, particularly when multivariable modeling is involved. Such packages assume that the data have resulted from simple random samples. However, when the survey design incorporates such features as clustering and stratification, the results of statistical analyses based on this assumption can be incorrect. The authors utilized data from the PAQUID (Personnes Agees Quid) study, collected periodically from 1988 to 1996, to illustrate the ease of performing a "design-based" (vs. a "model-based") analysis of complex survey data, and they compared the results obtained using both approaches. The PAQUID study is a stratified cluster sample of elderly community residents in the southwestern departments of Gironde and Dordogne, France. In the illustration presented-in which 3,777 community residents aged 65 years or older were selected to permit identification of baseline and lifetime factors that might be related to cognitive loss, dementia, and Alzheimer's disease--measures of association (such as odds ratios and their associated standard errors) were comparable for both analytical strategies. However, this may not be the case for other examples. Descriptive measures (such as estimates of means and proportions) may be more seriously compromised by the decision to ignore the sampling design. The availability of modern statistical packages with survey analysis capabilities should encourage data analysts to perform design-based analyses whenever possible.
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Cognitive process in preclinical phase of dementia.
Several recent prospective studies have demonstrated the existence of a preclinical stage of dementia, identifiable by neuropsychological assessment showing impairments with a great variety of cognitive tests. However, test scores are often colinear, largely because common cognitive components are involved in different tests; in spite of an apparent heterogeneity, it is still possible that a common cognitive component may be responsible for the deterioration shown in different tests in the preclinical phase. We studied the cognitive performances of 1159 elderly residents in the PAQUID (Personnes Agées quid) cohort, at a fixed lag time of 2 years before the clinical diagnosis of dementia. Seven neuropsychological tests were administered (Mini-Mental Status Examination, Benton Visual Retention Test, Wechsler Paired-Associates Test, Isaacs Set Test, Zazzo's Cancellation Task, Digit Symbol Substitution Test and Wechsler Similarities Test). Among the initially non-demented 1159 subjects, 25 developed a dementia 2 years later, of whom 16 were classified as cases of Alzheimer's disease. In order to dissect the multicolinearity of the tests we used a multivariate approach with principal component analysis (PCA). The patients' loading on each of the first four PCA factors were subsequently correlated with the risk of dementia and Alzheimer's disease 2 years later. The logistic regression with backward stepwise selected only the first factor as an independent predictor of dementia or Alzheimer's disease. Analysis shows that there are good reasons to suspect that the first PCA factor represents a general factor corresponding to aspects of control in the tasks used. Our results therefore seem to show that preclinical deficits in dementia and Alzheimer's disease reflect the deterioration of a general cognitive factor, which may be interpreted as the disturbance of central, control processes.
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