García-Domínguez 2026 — Strategic review of objective FM biomarkers and digital phenotyping

One-paragraph summary

Narrative review consolidating the emerging biomarker and digital-phenotyping landscape for fibromyalgia, framed explicitly around the transition from subjective symptom-criteria-based diagnosis to objective, data-driven, biomarker-anchored disease classification. Five categories of promising biomarkers are described: (1) neuroimaging indicators of altered pain processing; (2) neuroinflammatory signatures in CSF and blood; (3) dysregulated neuroendocrine and autonomic patterns; (4) metabolomic and transcriptomic molecular profiles; (5) digital phenotyping via wearable sensors, ecological momentary assessment, and machine learning-based symptom clustering. The integrative claim is that combining biological and digital metrics could enable a shift from subjective to objective FM classification, facilitating earlier diagnosis, reduced diagnostic delay, and improved therapeutic targeting. For the FM project, this review is a strategic context anchor for the retinal-biomarker-diagnostic-priority document: it independently confirms that the field is moving in the direction the project has prioritized (objective biomarker development), and supplies a categorization framework for situating the project's retinal-imaging substrate (which falls under neuroimaging + autonomic-pattern indicators) alongside the project's blood biomarker work (Dogan 2026 P2RX1/P2RY2/GRIN1; Fundaun 2026 NfL; Massó 2026 anti-GFAP; Seefried 2025 anti-SGC IgG). The review's diagnostic-stigma reduction framing aligns with the project's explicit secondary purpose for the retinal biomarker work.

Claims as triples

• objective_biomarker_diagnostics — emerging_in → fibromyalgia_field [trajectory observation across multiple biomarker types; confidence: emerging]
• digital_phenotyping — predicts → fibromyalgia [machine-learning-based symptom-clustering approaches surveyed; confidence: bridging]
• neuroinflammation_glial — present_in → fibromyalgia [CSF + blood neuroinflammatory signatures cited; confidence: emerging — reinforces existing project triple]
• autonomic_dysregulation — predicts → fibromyalgia [HRV + neuroendocrine pattern biomarkers cited; confidence: emerging — reinforces existing project triple]
• metabolomics_signature — bridges → fibromyalgia [emerging molecular profiles; confidence: bridging]
• transcriptomic_signature — bridges → fibromyalgia [emerging molecular profiles; confidence: bridging — connects to Gowri Gopal 2026 hub-gene work already in project]
• subjective_diagnosis_paradigm — contradicts → objective_biomarker_paradigm [the field's transitional positioning the review argues for; confidence: emerging]

Methods note

Narrative review — no new primary data. Single-author paper (García-Domínguez, Universidad de Cádiz). Synthesizes published biomarker and digital-phenotyping work into a framework for objective FM diagnosis. Reference set covers neuroimaging (fMRI, TSPO-PET), blood-based markers (cytokines, autoantibodies, metabolomic panels), wearable-sensor literature, and machine-learning classifier studies.

Limitations

• Narrative review without explicit methodology for paper selection — selection bias possible.
• Single-author review with limited institutional affiliations cited — less weight than multi-author consensus reviews.
• Does not extensively cover retinal imaging or ocular biomarkers (a gap the project's retinal-biomarker-diagnostic-priority document directly fills).
• Digital-phenotyping section is forward-looking; existing data on machine-learning FM classifiers is limited and methodologically heterogeneous.
• Treatment-implication claims are aspirational, not anchored to specific clinical-trial endpoints.

Open questions raised

• What is the optimal combination of biomarker categories (neuroimaging, blood, autonomic, digital) for FM diagnostic discrimination at population scale?
• Does adding retinal imaging (the project's priority modality) to existing biomarker panels improve diagnostic AUC beyond blood + brain imaging alone? (Q-Re-11 in project open questions.)
• How does digital phenotyping (wearables, EMA) interact with biological biomarkers — are they redundant, complementary, or stratifying?
• What is the regulatory pathway (FDA 510(k) vs De Novo) for a multi-modal FM diagnostic tool?

Triangulation notes

• Strategic context anchor for retinal-biomarker-diagnostic-priority.md: independently confirms the field's direction toward objective FM biomarkers — situates the project's retinal-imaging priority within a broader landscape rather than as an isolated framing.
• Connects to multiple existing project anchors: TSPO-PET (Coluzzi 2025), Dogan 2026 biomarker panel, anti-SGC IgG (Seefried 2025), Hou 2026 thalamocortical decoupling, Wirth & Scheibenbogen 2026 neurotransmitter-imbalance framework, Kerrebijn 2025 GWAS — all fall under the review's "promising biomarkers" categorization.
• Methodologically supports the project's biomarker-mapping cohort design: the review's call for integrated multi-modal biomarker panels is exactly what the cohort is being designed to enable.
• Underrepresents retinal imaging — a gap rather than a problem. The project's retinal-biomarker-diagnostic-priority document fills this gap and could plausibly become a citable extension of the García-Domínguez review framework once the project's retinal cohort data accumulates.
• Aligns with the diagnostic-stigma reduction framing of the project's advocacy page — both treat objective biomarker development as a means of moving FM from "diagnosis of exclusion" to "objectively measurable condition," with the implicit clinical-political payoff.

Bridges

• B-Re-6 (Objective FM diagnostic biomarkers ↔ retinal imaging substrate, NEW 2026-05-23). One endpoint anchored in García-Domínguez 2026's surveyed biomarker landscape; other endpoint at the project's retinal-imaging substrate (Garcia-Martin 2016, OCT modalities, Shi 2025 choroidal MC, Zhou 2026 gut-retina). Confidence: emerging. Closing: integrating retinal imaging into multi-modal FM diagnostic-tool validation studies, as proposed in the project's priority document §6.

Cure-path implications

The review is non-interventional but indirectly supports the project's cure-path program design: subtype-stratified treatment selection (the project's central cure-path framework) requires the objective biomarker substrate this review surveys. The retinal-imaging modality the project is prioritizing provides a non-invasive, low-cost, repeatedly-measurable component of the multi-modal panel the review argues is needed.