Room: Royal Lobby
Chair: Lina Kramer
External validation of population-based, multimodal prediction models for wellbeing in a depression and elderly cohort, Dirk Pelt (Vrije Universiteit), Philippe Habets (Amsterdam University Medical Center), Martijn Heymans (Amsterdam University Medical Center), Christiaan Vinkers (Amsterdam University Medical Center)
Abstract: Early identification of individuals at risk for mental health problems, as well as understanding the factors that promote wellbeing, is crucial for prevention and intervention strategies. To this end, we previously demonstrated (Pelt et al., 2024, Nature Mental Health) that wellbeing can be reliably predicted in a general population sample (Netherlands Twin Register; NTR) using psychosocial survey data, with modest contributions from environmental exposures, and no added value from genetic predictors. However, to enable broader, cost-effective applications, it is important to assess whether these prediction models are transportable to other populations, such as clinical or elderly cohorts. This study therefore aims to evaluate the external validity of wellbeing prediction models in the Netherlands Study of Depression and Anxiety (NESDA) and the Longitudinal Aging Study Amsterdam (LASA). This cross-cohort comparison seeks to determine whether models maintain predictive accuracy and to identify both shared and unique predictors across different life stages and mental health contexts. Objective environmental predictors were obtained by linking participants’ postal codes to registry-based exposures, providing information on, for example, air pollution, neighborhood characteristics, and greenspace availability (117 predictors). These were combined with 96 self-reported psychosocial features and 22 polygenic scores (PGS) covering a wide range of domains, and used as input for ordinal gradient boosting models predicting life satisfaction ratings.
Preliminary results on the survey data indicate that models trained on the NTR (ordinal AUC: .80 [.75 – .82] performed similarly in NESDA (o-AUC: .84 [.79 – .88]) but less well in LASA (o-AUC: .68 [.59 – .77]). In addition, the most important features were highly similar across cohorts, including neuroticism, partner status, and self-rated health. Results for models based on environmental and genetic data are forthcoming. These findings support the feasibility of transferring wellbeing prediction models across populations, with implications for developing targeted, personalized mental health interventions.
Do People Know What Breaks Their Hearts?, Fanny Tallgren (Erasmus Universiteit Rotterdam), Bram Wouterse (Radboud University Medical Center), Owen O’Donnell (Erasmus Universiteit Rotterdam)
Abstract: Accurate self-assessment of health risks is critical for optimal individual decision-making and prevention. This paper studies how accurately individuals assess their own risk of developing cardiovascular disease (CVD) and whether they appropriately weigh common risk factors. We link individual-level data from the Dutch LISS panel to longitudinal administrative microdata from Statistics Netherlands (CBS), including hospital discharge records, cause-of-death registers, and medication prescription data. This combined dataset enables us to compare subjective CVD risk perceptions with an objective risk function as well as actual CVD events occurring within five and ten years after the survey. We find that individuals substantially overestimate their CVD risk. However, subjective beliefs are positively associated with realised outcomes. Those who develop CVD on average report probabilities 5.7 percentage points higher than those who do not. We decompose this predictive power and show that most of it is explained by observable risk factors such as smoking, blood pressure, cholesterol, and diabetes. Private information such as family history plays a limited role. Most miscalibration arises from underestimating age-related risk increases. We further analyse how individuals interpret their change in CVD risk over time by comparing their five- and ten-year probability assessments. Despite actual CVD incidence doubling between the two periods, subjective probabilities increase only marginally, suggesting a “flatness bias” in risk perceptions over time. Furthermore, we find that those with lower education and numeracy skills display larger miscalibration, less appropriate weighting of risk factors, and weaker predictive power in their beliefs. Finally, we find that verbal statements about perceived risk (“”I think I am at high risk””) are also slightly misaligned with actual health outcomes. This study contributes to the literature on biases in disease risk perception by combining individual level subjective belief data with rich administrative data on realised health outcomes.”
Tracing Longevity Across Generations: Health and Disease Trajectories in Familial Longevity, Niels van den Berg (Leiden University Medical Center)
Abstract: The genetic component underlying longevity represents key mechanisms contributing to a life-long decreased mortality and morbidity risk. Identifying the mechanisms involved is challenging, mainly because of uncertainty in defining long-lived cases with heritable longevity amongst phenocopies and complex gene x environment interactions. Hence, we investigated the longevity trait and its transmission from one generation to the next. In large-scale family-tree data from Utah (UPDB) and the Netherlands (LINKS), we studied 20,360 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 314,819 individuals. We found strong evidence that longevity is transmitted as a quantitative genetic trait among the top 10% survivors of their birth cohort. The survival advantage amounted to 31% for individuals with top 10% surviving first and second-degree relatives in both databases and across two generations, even in the absence of non-long-lived parents. Subsequently, we developed the Longevity Relatives Count (LRC) score as an instrument to quantify the number of long-lived family members and observed that the survival advantage of study participants increased with each additional long-lived family member. Applying the LRC score to the LLS (Netherlands) and SEDD (Sweden; register data) showed that an increasing number of long-lived ancestors associates with an increasing delay in disease incidence (Fig1). As compared to their partners, members of long-lived families have a delayed onset of medication use, multimorbidity and blood-based profiles indicating improved metabolic health and low inflammation in mid-life. Our results indicate that an increasing number of long-lived ancestors marks a decade of healthspan extension, healthier metabolomics profiles, and can be used for more optimized case definitions. Building on these findings, future work will refine and generalize the LRC score into a broader family-based survival metric, enabling wider application across existing studies and supporting the disentanglement of gene x environment interactions in healthy aging and longevity.
The Absence of Genetic Risk for Cardiovascular Disease in Exceptional Survival (Longevity), Pedro Ferreira (Leiden University Medical Center), Marian Beekman (Leiden University Medical Center), Niels van den Berg (Leiden University Medical Center)
Abstract: Aging is the major risk factor for chronic diseases. Unlike the general population, members of long-lived families maintain exceptional health as they age. Healthy survival to extreme ages (longevity) clusters within families. However, research has not yet elucidated the underlying mechanisms of longevity. There are two important reasons for this: 1) the group with the highest heritability is often not studied and 2) the hypothesis-generating nature of most genetic studies requires larger study cohorts. In our previous work, we showed that members of the longest-lived families have a 10-year delayed onset of their first chronic diseases. We therefore hypothesize that the absence of genetic predisposition to chronic diseases is one of the key-mechanisms involved in longevity delayed disease onset. We investigated this hypothesis in the Leiden Longevity Study, a cohort with data from more than 400 long-lived families in 3-generations. To analyze our data, we constructed a set of PRSs covering the top 10 causes of death in the Netherlands. We observed that descendants of long-lived families have lower genetic risk for cardiovascular disease (CVD). Using accelerated failure time modeling, we further showed that around 20% of the delayed cardiovascular disease incidence in long-lived families is explained by CVD common genetic variants. We conducted gene-annotation enrichment analysis of the SNPs in the CVD PRS using DAVID and observed seven significantly enriched clusters. Finally, we constructed a novel cholesterol PRS based on the cholesterol metabolism cluster which significantly predicted time to all-cause mortality in a 90+ study population, covering 19 years of follow-up. Our study indicates that common variants related to cardiovascular diseases and cholesterol metabolism contribute to healthy aging. Furthermore, we demonstrate that investigating SNPs, identified in well-powered Genome Wide Association studies, associated with longevity-related endophenotypes can provide insight into the genetic architecture of the longevity phenotype itself.