Hélène Jacqmin-Gadda

Université Victor Segalen Bordeaux 2 | UB2 · Unité Epidémiologie et Biostatistique

Dementia currently affects about 50 million people worldwide, and this number is rising. Since there is still no cure, the primary focus remains on preventing modifiable risk factors such as cardiovascular factors. It is now recognized that high blood pressure is a risk factor for dementia. An increasing number of studies suggest that blood pressur...

INTRODUCTION: White matter hyperintensities (WMH), a major cerebral small vessel disease marker, may arise from different pathologies depending on their location. We explored clinical and genetic correlates of agnostically derived spatial WMH patterns in two longitudinal population-based cohorts (3C-Dijon, LIFE-Adult). METHODS: We derived seven WMH...

The utility of brain magnetic resonance imaging (MRI) for predicting dementia is debated. We evaluated the added value of repeated brain MRI, including atrophy and cerebral small vessel disease markers, for dementia prediction. We conducted a landmark competing risk analysis in 1716 participants of the French population‐based Three‐City Study to pr...

Importance Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential...

Background: The COVID-19 pandemic and lockdown have had negative effects on students mental health. However, little information is available regarding the frequencies of depressive symptoms and suicidal ideation during the post-pandemic period. We aimed to compare prevalence rates of depressive symptoms and suicidal ideation among university studen...

Importance: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. Objective: To disentangle the causal relation of several key vascular traits...

Given the high incidence of cardio and cerebrovascular diseases (CVD), and its association with morbidity and mortality, its prevention is a major public health issue. A high level of blood pressure is a well-known risk factor for these events and an increasing number of studies suggest that blood pressure variability may also be an independent ris...

Over the last years, there has been a considerable expansion of genome-wide association studies (GWAS) for discovering biological pathways underlying pathological conditions or disease biomarkers. These GWAS are often limited to binary or quantitative traits analyzed through linear or logistic models, respectively. In some situations, the distribut...

Background In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. When the studied risk factors are independent of time, including both pre- and post-inclusion events in the analyses, generally referred to as relying on an ambispective design, increases the statisti...

We propose a novel methodology to quantify the effect of stochastic interventions for a non-terminal intermediate time-to-event on a terminal time-to-event outcome. Investigating these effects is particularly important in health disparities research when we seek to quantify inequities in the timely delivery of treatment and its impact on patients'...

The epidemiological and societal burden of dementia is expected to increase in the coming decades due to the world population aging. In this context, the evaluation of the potential impact of intervention scenarios aiming at reducing the prevalence of dementia risk factors is an active area of research. However, such studies must account for the as...

Visit-to-visit blood pressure variability (BPV) has been identified in several recent studies as a risk factor for stroke, independently of the level of BP. If true, this finding could help to identify patients at higher risk of stroke and to develop new preventive strategies. However, studies on BPV are exposed to important methodological challeng...

Semicontinuous data, characterized by an excess of zeros followed by a non-negative and right-skewed distribution, are frequently observed in biomedical research. Different statistical models have been proposed to investigate the association of covariates with such outcome. Motivated by the search of genetic factors associated with Neutrophil Extra...

The epidemiological and societal burden of dementia is expected to increase in the coming decades due to the world population aging. In this context, the evaluation of the potential impact of intervention scenarios aiming at reducing the prevalence of dementia risk factors is an active area of research. However, such studies must account for the as...

In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. In an ambispective design, when the risk factors studied are independent of time, including both pre- and post-inclusion events in the analyses increases the statistical power but may lead to a selection bias. T...

The progression of dementia prevalence over the years and the lack of efficient treatments to stop or reverse the cognitive decline make dementia a major public health challenge in the developed world. Identifying subjects at high risk of developing dementia could improve the management of these patients and help selecting the target population for...

The sex/gender and aging-related cognitive decline association remains poorly understood due to inconsistencies in findings. Such heterogeneity could be attributable to the cognitive functions studied and study population characteristics, but also to a differential selection by drop-out and death between men and women. This work aims to evaluate th...

Background Thoroughly understanding the temporal associations between cognitive and functional dimensions along the dementia process is fundamental to define preventive measures likely to delay the disease’s onset. This work aimed to finely describe the trajectories of cognitive and functional declines, and assess their dynamic bidirectional relati...

We propose a novel methodology to quantify the effect of stochastic interventions on non-terminal time-to-events that lie on the pathway between an exposure and a terminal time-to-event outcome. Investigating these effects is particularly important in health disparities research when we seek to quantify inequities in timely delivery of treatment an...

IntroductionDespite the risks associated with their use, benzodiazepines remain used more widely than wisely. In this context, a better understanding of how their patterns of use can be associated with an increased risk of death appears essential. Indeed, the studies that investigated this association so far are inconsistent and question the influe...

Dementia is a major public health issue worldwide and chronic use of benzodiazepine, which is very frequent in northern countries, was found to be a risk factor of dementia. This work aims at evaluating the impact of a reduction in chronic use of benzodiazepine on the future burden of dementia in France. Using estimations of dementia incidence and...

Data on the long term evolution of renal function in essential hypertensive patients are scarce, showing a low incidence of end stage renal diseases but without information on how the renal function evolves. Our aim is to describe the long term evolution of renal function and possible trajectories in hypertensive patients. We included patients from...

Introduction Prodromal non-motor symptoms precede, often by decades, motor signs and diagnosis of Parkinson's disease. It is however still uncertain if cognitive changes belong to the spectrum of non-motor prodromal Parkinson's disease. Thanks to the very long-term follow-up of the PAQUID population-based cohort, we assessed trajectories of cogniti...

We suggest a regression approach to estimate the excess cumulative incidence function (CIF) when matched data are available. In a competing risk setting, we define the excess risk as the difference between the CIF in the exposed group and the background CIF observed in the unexposed group. We show that the excess risk can be estimated through an ex...

Aims This article sought to study the association between patterns of benzodiazepine (BZD) use and the risk of hip and forearm fractures in people aged 50 and 75 years or more. Methods In a representative cohort of the French National Health Insurance Fund of individuals aged 50 years or older (n = 106 437), we followed up BZD dispensing (reflecti...

Quantile regressions are increasingly used to provide population norms for quantitative variables. Indeed, they do not require any Gaussian assumption for the response and allow to characterize its entire distribution through different quantiles. Quantile regressions are especially useful to provide norms of cognitive scores in the elderly that may...

In biomedical research, various longitudinal markers measuring different quantities are often collected over time. For example, repeated measures of psychometric scores are very informative about the degradation process toward dementia. These trajectories are generally nonlinear with an acceleration of the decline a few years before the diagnosis a...

Alzheimer's disease gradually affects several components including the cerebral dimension with brain atrophies, the cognitive dimension with a decline in various functions and the functional dimension with impairment in the daily living activities. Understanding how such dimensions interconnect is crucial for AD research. However it requires to sim...

Joint models for recurrent and terminal events have not been yet developed for clustered data. The goals of our study are to develop a statistical framework for modelling clustered recurrent and terminal events and to perform dynamic predictions of the terminal event in family studies. We propose a joint nested frailty model for colonoscopy screeni...

In biomedical research, random changepoint mixed models are used to take into account an individual breakpoint in a biomarker trajectory. This may be observed in the cognitive decline measured by psychometric tests in the prediagnosis phase of Alzheimer's disease. The existence, intensity and duration of this accelerated decline can depend on indiv...

Pseudo-values provide a method to perform regression analysis for complex quantities with right-censored data. A further complication, interval-censored data, appears when events such as dementia are studied in an epidemiological cohort. We propose an extension of the pseudo-value approach for interval-censored data based on a semi-parametric estim...

Background Studies using health administrative databases (HAD) may lead to biased results since information on potential confounders is often missing. Methods that integrate confounder data from cohort studies, such as multivariate imputation by chained equations (MICE) and two-stage calibration (TSC), aim to reduce confounding bias. We provide new...

Background: Previous studies on the number of Parkinson's disease (PD) patients in the future based on projections of population size underestimated PD burden because they did not take into account the improvement of life expectancy over time. Objective: The objective of this study was to assess PD progression from 2010 to 2030 in France in terms o...

In line with declining trends in dementia incidence, this work thus aimed to compare the cognitive and functional evolution of two "generations" separated by 10 years and to evaluate the impact of specific risk factors on this evolution. This study was conducted on two "generations" of elderly individuals aged 78-88 years, who were included 10 year...

Alzheimer's disease gradually affects several components including the cerebral dimension with brain atrophies, the cognitive dimension with a decline in various functions and the functional dimension with impairment in the daily living activities. Understanding how such dimensions interconnect is crucial for AD research. However it requires to sim...

OBJECTIVES: To study the benefit of Ginkgo Biloba Extract (GBe) consumption on the long term risk of dementia and death in elderly people. DESIGN: The Paquid study is a population-based cohort with regular follow-up screenings up to twenty-two years and systematic detection of incident cases of dementia. Statistical analysis was conducted with an...

Chronic diseases are a growing public health problem due to the population aging. Their economic, social and demographic burden will worsen in years to come. Up to now, the method used to provide projections and assess the future disease burden makes a non-homogeneous Markov assumption in an illness–death model. Both age and calendar year have been...

As with many health constructs, cognition is difficult to measure accurately; it is assessed by multiple psychometric tests. Two approaches are commonly adopted to address this multivariate aspect in longitudinal analyses: the composite score approach summarizes the tests into a single outcome and subsequently analyzes its change; the multivariate...

Mixed models estimated by maximum likelihood and marginal models estimated by generalized estimating equations are the standard methods for the analysis of longitudinal data. However, their use is highly debated when attrition may be due to death. While some authors consider that mixed model estimates are interpretable only in an immortal cohort, w...

Objectives To analyse the impact of a risk factor on several epidemiological indicators of death and dementia; the example of sport practice is presented. Methods A population of 3670 non-demented subjects living at home and aged 65 and older from the PAQUID study were followed for 22 years. Sport practice was documented at baseline. Dementia (acc...

Mean lifetime with dementia according to age, sex, diploma, and sport practice status. (DOCX)

Bias due to selective mortality is a potential concern in many studies and is especially relevant in cognitive aging research because cognitive impairment strongly predicts subsequent mortality. Biased estimation of the effect of an exposure on rate of cognitive decline can occur when mortality is a common effect of exposure and an unmeasured deter...

The aging of the population is accompanied by a sharp rise of chronic disease prevalences, such as dementia. These diseases generally cannot be prevented or cured and persist over time, with a progressive deterioration of health, requiring specific care. To reduce the burden of these diseases, it is appropriate to propose interventions targeting di...

Background: Identifying modifiable lifestyle correlates of cognitive decline and risk of dementia is complex, particularly as few population-based longitudinal studies jointly model these interlinked processes. Recent methodological developments allow us to examine statistically defined sub-populations with separate cognitive trajectories and deme...

Dynamical Biostatistical Models presents statistical models and methods for the analysis of longitudinal data. The book focuses on models for analyzing repeated measures of quantitative and qualitative variables and events history, including survival and multistate models. Most of the advanced methods, such as multistate and joint models, can be ap...

Introduction: Few recent studies have suggested declining trends in dementia frequency. French cohorts with long follow-up allowed us to explore incidence evolution trends. Methods: Two different populations of subjects aged ≥65 years included in 1988-1989 (n = 1469) and 1999-2000 (n = 2104) were followed up over 10 years, with systematic assess...

Joint models are used in ageing studies to investigate the association between longitudinal markers and a time-to-event, and have been extended to multiple markers and/or competing risks. The competing risk of death must be considered in the elderly because death and dementia have common risk factors. Moreover, in cohort studies, time-to-dementia i...

Joint modelling of longitudinal and survival data is increasingly used in clinical trials on cancer. In prostate cancer for example, these models permit to account for the link between longitudinal measures of prostate-specific antigen (PSA) and the time of clinical recurrence when studying the risk of relapse. In practice, multiple types of relaps...

Introduction Dans les essais thérapeutiques, les marqueurs de substitution sont recherchés pour évaluer l’efficacité d’un traitement, en particulier lorsque le diagnostic de l’événement est difficile, la censure est importante, ou que le temps de survenue de l’événement est lointain. Dans le cancer de la prostate, par exemple, l’antigène spécifique...

Motivation Diseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative (ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, a...

Thanks to the growing interest in personalized medicine, joint modeling of longitudinal marker and time-to-event data has recently started to be used to derive dynamic individual risk predictions. Individual predictions are called dynamic because they are updated when information on the subject's health profile grows with time. We focus in this wor...

Joint models initially dedicated to a single longitudinal marker and a single time-to-event need to be extended to account for the rich longitudinal data of cohort studies. Multiple causes of clinical progression are indeed usually observed, and multiple longitudinal markers are collected when the true latent trait of interest is hard to capture (e...

Background: The Mini-Mental State Examination (MMSE) is widely used in population-based longitudinal studies to quantify cognitive change. However, its poor metrological properties, mainly ceiling/floor effects and varying sensitivity to change, have largely restricted its usefulness. We propose a normalizing transformation that corrects these pro...

Early detection of subjects at high risk of developing dementia is essential. By dealing with censoring and competing risk of death, we developed a score for predicting 10-year dementia risk by combining cognitive tests, and we assessed whether inclusion of cognitive change over the previous year increased its discrimination. Data came from the Fre...

With the emergence of rich information on biomarkers after treatments, new types of prognostic tools are being developed: dynamic prognostic tools that can be updated at each new biomarker measurement. Such predictions are of interest in oncology where after an initial treatment, patients are monitored with repeated biomarker data. However, in such...

Semicompeting risks and interval censoring are frequent in medical studies, for instance when a disease may be diagnosed only at times of visit and disease onset is in competition with death. To evaluate the ability of markers to predict disease onset in this context, estimators of discrimination measures must account for these two issues. In recen...

Cognitive lifestyle measures such as education, occupation, and social engagement are commonly associated with late-life cognitive ability although their associations with cognitive decline tend to be mixed. However, longitudinal analyses of cognition rarely account for death and dropout, measurement error of the cognitive phenotype, and differing...

A better knowledge of long-term trajectories of cognitive decline is a central feature of the study of the process leading to Alzheimer's dementia. Several factors may mitigate such decline, among which is education, a major risk factor for Alzheimer's disease. The aim of our work was to compare the pattern and duration of clinical trajectories bef...

The area under the time-dependent ROC curve (AUC) may be used to quantify the ability of a marker to predict the onset of a clinical outcome in the future. For survival analysis with competing risks, two alternative definitions of the specificity may be proposed depending of the way to deal with subjects who undergo the competing events. In this wo...

To quantify the ability of a marker to predict the onset of a clinical outcome in the future, time-dependent estimators of sensitivity, specificity, and ROC curve have been proposed accounting for censoring of the outcome. In this paper, we review these estimators, recall their assumptions about the censoring mechanism and highlight their relations...

To investigate the sensitivity of a large set of neuropsychological tests to detect cognitive changes due to prodromal Alzheimer's disease(AD); to compare their metrological properties in order to select a restricted number of these tests for the longitudinal follow-up of subjects with prodromal AD. 212 patients with mild cognitive impairment were...

Incidence of dementia increases sharply with age and, because of the increase in life expectancy, the number of dementia cases is expected to rise dramatically over time. Some studies suggest that controlling some modifiable risk factors for dementia like diabetes or hypertension could lower its incidence. However, as treating these vascular factor...

Background/aims: This study was designed to develop a practical risk score for predicting 5-year survival after the diagnosis of dementia. Methods: Using the Paquid Study (prospective, population-based, long-term cohort study), we created a prognosis score with incident cases of dementia and validated it in another prospective, population-based,...

Summary The estimation of future prevalences of chronic diseases is essential for public health policy. Using incidence estimates from cohort data and demographic projections for general mortality and population sizes, we propose a method based on a general illness-death model to make prevalence projections for chronic diseases. In contrast to prev...

Longitudinal studies are those in which the same variable is repeatedly measured at different times. These studies are more likely than others to suffer from missing values. Since the presence of missing values may have an important impact on statistical analyses, it is important that they should be dealt with properly. In this paper, we present “C...

Background: Using simple measures of cognition and disability in a prospective community-living cohort of normal elderly persons, the main objectives of our study were to distinguish short- and long-term predictors for dementia according to educational level and to propose a tool for early detection of subjects at high risk of dementia. Methods:...

Multivariate ordinal and quantitative longitudinal data measuring the same latent construct are frequently collected in psychology. We propose an approach to describe change over time of the latent process underlying multiple longitudinal outcomes of different types (binary, ordinal, quantitative). By relying on random-effect models, this approach...

Paquid (personnes âgées quid) is a population-based cohort specifically designed to study the epidemiology of brain aging and dependency in activities of daily living in elderly people. At baseline screening, 3.777 subjects older than 65 were randomly selected in 75 different parishes from Gironde and Dordogne, and two administrative districts arou...

Most statistical developments in the joint modelling area have focused on the shared random-effect models that include characteristics of the longitudinal marker as predictors in the model for the time-to-event. A less well-known approach is the joint latent class model which consists in assuming that a latent class structure entirely captures the...

The linear mixed model (LMM), which is routinely used to describe change in outcomes over time and its association with risk factors, assumes that a unit change in any predictor is associated with a constant change in the outcome. When it is used on psychometric tests, this assumption may not hold. Indeed, psychometric tests usually suffer from cei...

Subjective memory complaint (SMC) and restriction in cognitively-complex activities of daily living (such as instrumental ADL) are two early symptoms observed in the prodromal phase of dementia and may represent useful alarm signals for general practitioners for an increased risk of subsequent dementia. We here studied in a large population-based e...