Assessing and refining a metabolite-based distress score for use in different populations within three US cohorts

Q: What are the key findings of this study?

A derived 33-metabolite multi-ethnic distress score (MDS-ME) was associated with higher odds of depression in Black participants (OR 1.45 per 1-SD increase), improving generalization across diverse populations.

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Depression and Psychological Distress (n=7428). Intervention: Multi-ethnic metabolite-based distress score (MDS-ME) vs. Per 1-SD increment in score. Primary outcome: Probable depression status (OR 1.45, 95% CI 1.04-2.03).

Q: What does this research mean for the field?

A derived 33-metabolite multi-ethnic distress score is significantly associated with higher odds of depression in Black individuals while maintaining strong associations in White individuals, improving generalizability across diverse populations. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Tianyi Huang; Yiwen Zhu; Raji Balasubramanian; Andrea L. Roberts; Clary B. Clish; Julián Ávila-Pacheco; Jerome I. Rotter; Xiuqing Guo; Jie Yao; Yii‐Der Ida Chen; Stephen S. Rich; Kent D. Taylor; Alexis C. Wood; W. Craig Johnson; Katherine Hoff Shutta; Kathryn M. Rexrode; Aladdin H. Shadyab; Su Yon Jung; JoAnn E. Manson; Susan E. Hankinson; Laura Diane Kubzansky

doi:10.64898/2026.09.10.26362734

Key result

Multi-ethnic metabolite distress score links to ~45% higher depression odds per SD in Black adults.

OR 1.45
95% CI 1.04-2.03
n=7,428

Figures

Why the study?

Psychological distress is linked to metabolic alterations contributing to cardiometabolic outcomes, but the metabolite-based distress score (MDS) was developed mainly in White women and its applicability to men and Black individuals was unclear.

Does a multi-ethnic metabolite-based distress score (MDS-ME) accurately associate with prevalent depression across diverse populations, including Black individuals and men?

Key Points

To determine whether a metabolite-based distress score developed in White women associates with depression in Black individuals, and to refine the score for multi-ethnic populations.
Evaluated plasma metabolomics and baseline depression status among 2,477 White and 1,625 Black participants from the Multi-Ethnic Study of Atherosclerosis (MESA).
Conducted an agnostic metabolomic screening in a 70% random discovery subset of Black participants (n=1,140) and applied LASSO selection across 63 candidates to develop a multi-ethnic score (MDS-ME).
Tested the 33-metabolite MDS-ME in an independent withheld sample of 485 Black MESA participants and independent samples from the Women's Health Initiative (WHI) and Nurses' Health Study (NHS).
The original 20-metabolite score showed a stronger association with prevalent depression in White (OR: 1.93, 95% CI: 1.71, 2.19) than in Black (OR: 1.13, 95% CI: 0.97, 1.33) MESA participants.
The refined 33-metabolite MDS-ME was more strongly associated with depression in Black participants (OR: 1.45, 95% CI: 1.04, 2.03) while maintaining strong performance in White participants (OR: 1.81, 95% CI: 1.60, 2.04).
Meta-analysis across Black participants in MESA, WHI (OR: 1.34, 95% CI: 0.85, 2.21), and NHS (OR: 1.20, 95% CI: 0.69, 2.06) demonstrated a pooled OR of 1.36 (95% CI: 1.07, 1.74; I2=0%, p for heterogeneity=0.84).

Study Design

Type

Observational (n=7,428)

Multicenter

Yes

Structured PICO

Does a multi-ethnic metabolite-based distress score (MDS-ME) accurately associate with prevalent depression across diverse populations, including Black individuals and men?

P

Population

7,428 diverse participants from three major US cohorts (MESA, WHI, NHS) evaluated for depression status and cross-sectional plasma metabolomic profiles.

E

Exposure

Multi-ethnic metabolite-based distress score (MDS-ME) comprising 33 metabolites, derived using LASSO logistic regression and evaluated for association with depression.

C

Comparator

Original 20-metabolite distress score (MDS) derived predominantly in White women.

O

Outcome

Depression status at baseline, defined by current antidepressant use, a validated depressive symptom score above an established cutoff (CES-D >=16 or MHI-5 <=52), or self-reported history of depressed mood/diagnosis.patient reported

Main Result

Odds Ratio: 1.45 (95% CI 1.04–2.03)

Incorporating metabolites identified in diverse populations enhances the generalizability of a metabolite-based distress score linked to depression and subsequent cardiometabolic risk across different racial groups.

Limitations

Not all metabolites were available across all three cohorts, requiring the use of reduced proxy scores in WHI and NHS.
The associations in the WHI and NHS replication subsets of Black women did not independently reach statistical significance due to small sample sizes.
Data limits on covariates required some inconsistencies in adjustment models across the three cohorts.
Cross-sectional measurement limits the ability to draw definitive causal inferences regarding depression and metabolomics.
Limited sample size for Black participants may have reduced power for metabolite discovery and replication
Differing platforms and limited coverage of available metabolites across WHI and NHS replication cohorts
Heterogeneity of the depression phenotype in Black participants influenced by broader social and environmental factors

Implication

May extend metabolite-based depression assessment to diverse groups; hypothesis-generating and requires prospective validation before clinical adoption.

Abstract

Introduction: Psychological distress is associated with metabolic alterations that contribute to adverse cardiometabolic outcomes across diverse populations. We previously developed a metabolite-based distress score (MDS) in predominantly White women. Because men and Black individuals suffer high rates of cardiometabolic disease, we evaluated whether the MDS is similarly associated with depression in these populations, and derived a multi-ethnic MDS (MDS-ME) among Black individuals with replications in independent samples. Methods: Data were from three U.S. cohorts, the Multi-Ethnic Study of Atherosclerosis (MESA), Women's Health Initiative (WHI), and Nurses' Health Study (NHS), evaluated in 4 stages. Stages 1-3 included 2,477 White and 1,625 Black MESA participants with depression status data and plasma metabolomics assessed at baseline. Stage 1: We calculated the MDS and examined its association with depression status. Stage 2: We conducted an agnostic analysis among a 70% random subset of Black participants to identify additional relevant metabolites. Stage 3: We derived an MDS-ME in Black participants. Stage 4: We evaluated the MDS-ME using independent samples from all three cohorts. Results: The previously validated 20-metabolite MDS showed stronger associations with prevalent depression in White (OR: 1.93, 95% CI: 1.71, 2.19) versus Black (OR: 1.13, 95% CI: 0.97, 1.33) MESA participants. Associations were generally similar in men and women. The MDS-ME comprised 33 metabolites, and relative to the MDS was more strongly associated with depression in Black participants (OR: 1.45; 95% CI: 1.04, 2.03), with associations also evident in White participants (OR: 1.81; 95% CI: 1.60, 2.04). The MDS-ME was similarly associated with depression in Black women in WHI and NHS. Conclusion: Results suggest that incorporating metabolites identified in Black participants enhances the utility and generalizability of the MDS across more diverse populations.

Discussion

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Cite This Study

Huang et al. (2026) conducted an observational in Depression and Psychological Distress (n=7,428). Multi-ethnic metabolite-based distress score (MDS-ME) vs. Per 1-SD increment in score was evaluated on Probable depression status (OR 1.45, 95% CI 1.04-2.03). A derived 33-metabolite multi-ethnic distress score (MDS-ME) was associated with higher odds of depression in Black participants (OR 1.45 per 1-SD increase), improving generalization across diverse populations.

synapsesocial.com/papers/6ad0fd4715427f6a84040640 https://doi.org/10.64898/2026.09.10.26362734

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Assessing and refining a metabolite-based distress score for use in different populations within three US cohorts

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Assessing and refining a metabolite-based distress score for use in different populations within three US cohorts

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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