TY - JOUR
T1 - The risks of biomarker-based epidemiology
T2 - Associations of circulating calcium levels with age, mortality, and frailty vary substantially across populations
AU - Cohen, Alan A.
AU - Legault, Véronique
AU - Fuellen, Georg
AU - Fülöp, Tamàs
AU - Fried, Linda P.
AU - Ferrucci, Luigi
N1 - Funding Information:
This work was supported by the Canadian Institutes of Health Research (CIHR, grant numbers 119485 and 145585 ). AAC is also supported by a CIHR New Investigator Salary Award and is a member of the Fonds de recherche du Québec – Santé funded Centre de recherche du CHUS and Centre de recherche sur le vieillissement. GF is supported by the European Union's Horizon 2020 research and innovation program (grant number 633589 ).
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Recent studies have shown contradictory associations between calcium levels and health outcomes. We suspected these conflicting results were the consequence of more general issues with how biomarkers are analyzed in epidemiological studies, particularly in the context of aging. To demonstrate the risks of typical analyses, we used three longitudinal aging cohort studies and their demographic subsets to analyze how calcium levels change with age and predict risk of mortality and frailty. We show that calcium levels either increase or decrease with age depending on the population, and positively or negatively predict frailty depending on the population and analysis; both age and frailty results showed substantial heterogeneity. Mortality analyses revealed few significant associations but were likely underpowered. Variation in population composition (demographics, diseases, diet, etc.) leads to contradictory findings in the literature for calcium and likely for other biomarkers. Epidemiological studies of biomarkers are particularly sensitive to population composition both because biomarkers generally have non-linear and often non-monotonic relationships with other key variables, notably age and health outcomes, and because there is strong interdependence among biomarkers, which are integrated into complex regulatory networks. Consequently, most biomarkers have multiple physiological roles and are implicated in multiple pathologies. We argue that epidemiological studies of aging using biomarkers must account for these factors, and suggest methods to do this.
AB - Recent studies have shown contradictory associations between calcium levels and health outcomes. We suspected these conflicting results were the consequence of more general issues with how biomarkers are analyzed in epidemiological studies, particularly in the context of aging. To demonstrate the risks of typical analyses, we used three longitudinal aging cohort studies and their demographic subsets to analyze how calcium levels change with age and predict risk of mortality and frailty. We show that calcium levels either increase or decrease with age depending on the population, and positively or negatively predict frailty depending on the population and analysis; both age and frailty results showed substantial heterogeneity. Mortality analyses revealed few significant associations but were likely underpowered. Variation in population composition (demographics, diseases, diet, etc.) leads to contradictory findings in the literature for calcium and likely for other biomarkers. Epidemiological studies of biomarkers are particularly sensitive to population composition both because biomarkers generally have non-linear and often non-monotonic relationships with other key variables, notably age and health outcomes, and because there is strong interdependence among biomarkers, which are integrated into complex regulatory networks. Consequently, most biomarkers have multiple physiological roles and are implicated in multiple pathologies. We argue that epidemiological studies of aging using biomarkers must account for these factors, and suggest methods to do this.
KW - Aging biomarkers
KW - Calcium
KW - Frailty
KW - Physiological complexity
KW - Population composition
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U2 - 10.1016/j.exger.2017.07.011
DO - 10.1016/j.exger.2017.07.011
M3 - Review article
C2 - 28723411
AN - SCOPUS:85025454697
SN - 0531-5565
VL - 107
SP - 11
EP - 17
JO - Experimental Gerontology
JF - Experimental Gerontology
ER -