Highlight
- Measured and unmeasured life-course factors explain 24.5-86.3% of chronic disease accumulation across eight major organ systems.
- Unmeasured factors contribute substantially, accounting for most variance in chronic disease burden.
- Key modifiable measured drivers include body mass index (BMI), fasting blood glucose, and systolic blood pressure.
- The findings underscore the complexity of multimorbidity and the need for further research on hidden determinants.
Study Background
Chronic diseases often co-occur, affecting multiple organ systems simultaneously or sequentially, leading to multimorbidity. While individual risk factors have been linked to specific diseases, understanding how life-course factors cumulatively influence disease accumulation across organ systems remains limited. This knowledge gap presents a barrier to developing holistic preventive strategies and personalized interventions. The present longitudinal birth cohort study from Helsinki University Central Hospital seeks to dissect the contributions of both measured and unmeasured life-course factors to chronic disease burden across eight major organ systems over a 30-year period.
Study Design
This observational, population-based longitudinal study traced 2003 individuals born between 1934 and 1944 at Helsinki University Central Hospital. Participants were followed up from birth, with data collected through clinical assessments, hospital inpatient and outpatient records, and child welfare clinic visits extending into late midlife and beyond up to 2017. Chronic diseases were tracked across eight organ systems: cardiovascular, gastrointestinal, metabolic, musculoskeletal, respiratory, neurological, sensory, and others.
Measured life-course factors included demographic variables (age, sex), early life conditions, adult lifestyle patterns, clinical characteristics, biomarker profiles (including BMI, blood glucose, and blood pressure), and socioeconomic status. Unmeasured factors were statistically estimated to capture influences beyond the measured variables, recognizing that unknown or latent variables may impact disease trajectories. Multidimensional linear mixed-effects models accounted for the interdependence of diseases across organ systems while quantifying the relative contribution of measured and unmeasured factors to disease accumulation.
Key Findings
The extent to which life-course factors explained chronic disease accumulation varied by organ system, with explanatory power ranging from 24.5% to 86.3%. Across all systems combined, measured and unmeasured factors accounted for 48.3% of the variance in total disease burden. Notably, unmeasured factors accounted for 20.1% to 82.0% of this variance, indicating that a large component of disease risk remains unidentified by conventional measures.
Among measured factors, clinical characteristics and biomarkers collectively explained the greatest proportion of disease accumulation (mean 30.3%), underscoring the importance of physiological markers in multimorbidity risk prediction. Age independently accounted for approximately 22.2% of variance, confirming that aging is a strong driver of multimorbidity across organ systems.
Early life factors (20.8%), adult lifestyle factors (15.8%), socioeconomic status (8.5%), and sex (2.4%) contributed variably depending on the organ system affected.
Detailed associations revealed that:
- Each decade of aging increased disease accumulation by 1.28 to 2.06 times.
- A 1-standard deviation increase in BMI was linked to a 1.28 to 1.72-fold increase in diseases affecting cardiovascular, gastrointestinal, metabolic, musculoskeletal, and respiratory systems.
- A 1-standard deviation increase in fasting blood glucose predicted a 1.14 to 1.35 times increase in cardiovascular, metabolic, neurological, and sensory diseases.
- A 1-standard deviation increase in systolic blood pressure was associated with a 1.16 times increase in cardiovascular diseases and a 1.39 times increase in metabolic diseases.
The prominence of modifiable biomarkers like BMI, glucose, and blood pressure points to actionable targets for prevention and disease management to curtail multimorbidity progression.
Expert Commentary
This comprehensive longitudinal study highlights the intricate interplay between life-course factors and chronic disease accumulation across organ systems. The large unexplained variance attributed to unmeasured factors suggests that genetic predispositions, environmental exposures, psychosocial stressors, epigenetic modifications, and healthcare access disparities may substantially influence multimorbidity development.
The findings emphasize the need for more granular, integrative research employing multi-omics approaches, environmental monitoring, and detailed psychosocial assessments to identify these hidden determinants. Moreover, the strong effect of metabolic markers aligns with current understanding that systemic metabolic dysfunction underpins diverse chronic diseases, reinforcing the imperative for early metabolic risk screening and interventions.
Limitations include potential cohort-specific factors related to the Finnish population born in the 1930s–40s, which may affect generalizability to other populations. Also, measurement limitations and evolving diagnostic criteria over decades can impact disease ascertainment consistency.
Conclusion
This longitudinal birth cohort study elucidates that measured and largely unmeasured life-course factors collectively explain up to three-quarters of chronic disease accumulation across eight major organ systems. While aging and clinical biomarkers such as BMI, blood glucose, and blood pressure significantly drive multimorbidity, substantial unexplained variance remains. The study underscores the complexity of chronic disease interplay and the critical need for further research to elucidate hidden determinants to inform comprehensive prevention and management strategies.
Funding
The study was supported by Finska Läkaresällskapet.
References
Haapanen MJ, Niku J, Mikkola TM, Vetrano DL, Calderón-Larrañaga A, Dekhtyar S, Kajantie E, von Bonsdorff MB, Eriksson JG. Observed and hidden factors underlying the accumulation of chronic diseases across eight major organ systems: a longitudinal birth cohort study. Lancet Healthy Longev. 2025 May;6(5):100710. doi: 10.1016/j.lanhl.2025.100710. Epub 2025 May 22. PMID: 40414229.
