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.
AIC is commonly used for model selection but the precise value of AIC has no direct interpretation. We are interested in quantifying a difference of risks between two models. This may be useful for ...both an explanatory point of view or for prediction, where a simpler model may be preferred if it does nearly as well as a more complex model. The difference of risks can be interpreted by linking the risks with relative errors in the computation of probabilities and looking at the values obtained for simple models. A scale of values going from negligible to large is proposed. We propose a normalization of a difference of Akaike criteria for estimating the difference of expected Kullback-Leibler risks between maximum likelihood estimators of the distribution in two different models. The variability of this statistic can be estimated. Thus, an interval can be constructed which contains the true difference of expected Kullback-Leibler risks with a pre-specified probability. A simulation study shows that the method works and it is illustrated on two examples. The first is a study of the relationship between body-mass index and depression in elderly people. The second is the choice between models of HIV dynamics, where one model makes the distinction between activated CD4+ T lymphocytes and the other does not.
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HIV dynamical models are often based on non-linear systems of ordinary differential equations (ODE), which do not have an analytical solution. Introducing random effects in such models leads to very ...challenging non-linear mixed-effects models. To avoid the numerical computation of multiple integrals involved in the likelihood, a hierarchical likelihood (h-likelihood) approach, treated in the spirit of a penalized likelihood is proposed. The asymptotic distribution of the maximum h-likelihood estimators (MHLE) for fixed effects is given. The MHLE are slightly biased but the bias can be made negligible by using a parametric bootstrap procedure. An efficient algorithm for maximizing the h-likelihood is proposed. A simulation study, based on a classical HIV dynamical model, confirms the good properties of the MHLE. The method is applied to the analysis of a clinical trial.
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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. Am J Epidemiol 1998;148:298–306.
Ablation of the slow pathway has been performed to eliminate atrioventricular (AV) nodal reentrant tachycardia (AVNRT) either by a surgical approach or by using radiofrequency catheter technique ...guided by retrograde slow pathway activation mapping. From previous experience of midseptal and posteroseptal mapping, we were aware of the existence of peculiar slow potentials in most humans. Postulating their role in AVNRT, we studied these potentials and the effects of radiofrequency energy.
Sixty-four patients (mean age, 48 +/- 19 years) with the usual form of AVNRT were studied. Slow, low-amplitude potentials were recorded when using the anterograde AV conducting system. Slow potentials occupied all (giving a continuum of electrograms) or some of the time between the atrial and ventricular electrograms. Their most specific patterns were their progressive response to increasing atrial rates, which resulted in a dramatic decline in amplitude and slope, a corresponding increase in duration, and a separation from preceding atrial potentials until the disappearance of any consistent activity. Slow potentials were recorded along a vertical band at the mid or posterior part of the septum near the tricuspid annulus. Radiofrequency energy applied at the slow potential site resulted in interruption of induced tachycardia within a few seconds and rendered tachycardia noninducible in all patients. A median of two impulses was delivered to each patient. In 69% of patients, postablation atrial stimulation cannot achieve a long atrial-His interval, which previously was critical for tachycardia induction or maintenance. No patient had AVNRT over a follow-up period of 1-16 months, and all had preserved AV conduction. In all except two patients, the PR interval was unchanged. In 47 patients, long-term electrophysiological studies confirmed the efficacy of ablation and the nonreversibility of results by isoproterenol; however, echo beats remained inducible in 40% of patients.
An area showing slow potentials is present at the perinodal region in humans. In patients with AVNRT, application of radiofrequency energy renders tachycardia noninducible through the preferential modification of the anterograde slow pathway. With present clinical methods, the exact origin and significance of these physiological potentials cannot be specified.
To analyze the relationship between marital status and risk of AD or dementia.
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.
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).
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.
During primary HIV infection, the kinetics of plasma virus concentrations and CD4+ cell counts is very complex. Parametric and nonparametric models have been suggested for fitting repeated ...measurements of these markers. Alternatively, mechanistic approaches based on ordinary differential equations have also been proposed. These latter models are constructed according to biological knowledge and take into account the complex non-linear interactions between viruses and cells. However, estimating the parameters of these models is difficult. A main difficulty in the context of primary HIV infection is that the date of infection is generally unknown. For some patients, the date of last negative HIV test is available in addition to the date of first positive HIV test (seroconverters). In this paper we propose a likelihood-based method for estimating the parameters of dynamical models using a population approach and taking into account the uncertainty of the infection date. We applied this method to a sample of 761 HIV-infected patients from the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE).
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In testing genetic linkage using large or complex pedigrees, robust methods may be preferred to the Lod-score method. The affected-pedigree-member method is robust but does not use the information ...available in nonaffected subjects, which results in a loss of power. We propose a new test of genetic linkage based on a score test of homogeneity derived from a random effect model. The statistic is simple and uses only pairs of subjects. In contrast with the affected-pedigree-method, it uses all the available pairs and does not depend on the marker alleles frequencies. A rank version of this weighted pairwise correlation statistic is proposed, its exact first and second moment derived. We show that for age-dependent diseases, it provides a simple nonparametric test.
Alcoholism is a possible cause of dementia, mainly through associated nutritional deficiencies and, rarely, through acute direct toxicity. However alcohol consumption was not found to be a risk ...factor in previous epidemiologic studies. We prospectively studied 3,777 community residents aged 65 and over, in the districts of Gironde and Dordogne. Average daily alcoholic consumption was recorded at baseline. Incident cases of dementia and Alzheimer's disease were screened at follow-up with explicit criteria. At 3 years, 2,273 subjects not demented at baseline were still available for follow-up. Wine was the only alcoholic beverage reported by more than 95 p. 100 of regular drinkers. In the 318 subjects drinking 3 to 4 standard glasses per day (> 250 and up to 500 ml), categorized as moderate drinkers, the crude odds ratio (OR) was 0.18 for incident dementia (p < 0.01) and 0.25 for Alzheimer's disease (p < 0.03), as compared to the 971 non-drinkers. After adjusting for age, sex, education, occupation, baseline MMSE and other possible confounders, the ORs were respectively 0.19 (p < 0.01) and 0.28 (p < 0.05). In the 922 mild drinkers (< 1 to 2 glasses per day) there was a negative association only with AD, after adjustment (OR = 0.55; p < 0.05). The inverse relationship between moderate wine drinking and incident dementia was explained neither by known predictors of dementia nor by medical, psychological or socio-familial factors. Considering also the well documented negative associations between moderate wine consumption and cardiovascular morbidity and mortality in this age group, it seems that there is no medical rationale to advise people over 65 to quit drinking wine moderately, as this habit carries no specific risk and may even be of some benefit for their health. Advising all elderly people to drink wine regularly for prevention of dementia would be however premature at this stage.
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