The Precision Mito- Mito Map COMPASS Study

COMPASS is a prospective, remote, longitudinal observational cohort study designed to externally evaluate the measurement behavior and longitudinal criterion validity of the frozen canonical Mito Map Energy Score. Participants complete seven matched assessments from baseline through week 12.

The primary objective is to estimate the average within-person association between changes in the Energy Score and changes in a separately constructed objective home-function anchor based on protocolized grip-strength and five-times sit-to-stand measurements. The primary anchor excludes fatigue and shares no inputs with the Energy Score.

The initial enrollment target is 400 adults across seven prespecified cohorts: healthy comparison; broad mitochondrial disease; POLG-related disease; post-infectious or autonomic illness; cancer and cancer survivorship; other persistent energy-limiting conditions; and Lyme disease or post-treatment Lyme disease syndrome. Participants meeting the dedicated POLG cohort definition are assigned to that cohort rather than the broad mitochondrial cohort. The 50-person POLG cohort is prespecified for descriptive and exploratory subgroup analyses and is not separately powered for confirmatory POLG-specific, variant-level, prognostic, or treatment-response claims.

Secondary objectives include characterizing between-person association, test-retest reliability, adherence, missingness, assessment failures, participant burden, and safety during home measurement. Exploratory analyses will examine prediction of the next functional assessment, longitudinal transition yield, naturally occurring exposure changes, optional wearable measures, optional Flic symptom, context, and confirmed intervention markers, and variation across the seven cohorts. Cohort comparisons are exploratory and are intended to help distinguish shared and condition-specific patterns across complex energy-limiting illnesses.

The study is non-interventional. It does not assign medications, supplements, devices, exercise, diet, or other treatment. Results will not establish diagnosis, treatment efficacy, clinical utility, prognosis, mitochondrial ATP production, or a minimum clinically important difference. The same dataset will not be used both to tune the Energy Score or functional anchor and to claim locked external validation.

• Mito Map Energy Score and Home Functional Assessments (Other): Observational measurement package completed at baseline and approximately every two weeks through week 12. It includes the canonical Mito Map Energy Score and protocolized home measures of objective function, including grip strength and five-times sit-to-stand when safe and feasible. Participants are not assigned treatment, and these measurements are not used for diagnosis or clinical decision-making.

Primary outcomes

• Within-participant association between canonical Energy Score and objective home function composite [Baseline through week 12]: Coefficient for within-person centered canonical Energy Score in a participant fixed-effects model of the participant-self-administered, unblinded objective home function composite, adjusted for centered elapsed week and locked measurement-condition covariates, with participant-cluster-robust sandwich standard errors. The anchor is algorithmically independent because it shares no inputs with the Energy Score; it is not independently administered or blinded.

Secondary outcomes

• Within-participant association between canonical Energy Score and full Measured Function Score [Baseline through week 12]: Fixed-effect coefficient for within-person centered canonical Energy Score in the longitudinal model of the locked Measured Function Score that includes fatigue. Interpretation will explicitly acknowledge shared symptom inputs and possible circularity.
• Within-participant association between canonical Energy Score and grip strength [Baseline through week 12]: Fixed-effect coefficient for within-person centered canonical Energy Score in the longitudinal model of maximum valid grip force from three protocolized attempts. Grip force is natural-log transformed; device, hand, and measurement-condition covariates are recorded.
• Within-participant association between canonical Energy Score and five-times sit-to-stand performance [Baseline through week 12]: Fixed-effect coefficient for within-person centered canonical Energy Score in the longitudinal model of natural-log five-times-sit-to-stand seconds, direction aligned so higher values indicate better performance.
• Energy Score test-retest reliability during clinically stable intervals [Adjacent assessments from baseline through week 12]: Absolute-agreement single-measure ICC(A,1) from a two-way mixed-effects model and standard error of measurement for adjacent assessments with no acute infection, hospitalization or urgent visit, function-altering medication change in the prior 7 days, unusual exertion in the prior 48 hours, or major measurement-protocol deviation.
• Assessment completion [Baseline and Weeks 2, 4, 6, 8, 10, and 12]: Number and percentage of seven scheduled assessments completed with usable matched canonical Energy Score and objective functional data. Reasons for missing or unusable assessments will be summarized.
• Adverse events during home measurement [From informed consent through participant closeout after the Week 12 assessment (approximately 12 weeks of scheduled follow-up from baseline).]: Counts and percentages of participants with adverse events and serious adverse events temporally associated with study measurement procedures, summarized by event type, severity, relatedness, and action taken.

Other outcomes

• Between-participant association between mean Energy Score and mean objective home function [Baseline through week 12]: Association between each participant's mean canonical Energy Score and mean objective home function composite, reported separately from the primary within-person estimand.
• Incremental prediction of the next objective functional assessment [Weeks 2 through 12]: Difference in root mean squared prediction error under participant-grouped 10-fold cross-validation between a model containing current objective function and elapsed time and a model that additionally contains current canonical Energy Score. This exploratory analysis does not establish prognosis or clinical utility.
• Variation in the primary association across prespecified cohorts [Baseline through week 12]: Energy Score-by-cohort interaction estimates and cohort-specific coefficients with confidence intervals. The study is not powered for interaction detection; results are exploratory, and absence of significance will not be interpreted as equivalence between cohorts.
• Quality-qualified longitudinal transition yield [Adjacent scheduled assessments from baseline through week 12]: Number and percentage of up to six adjacent scheduled assessment intervals per participant that qualify. Both assessments must occur within the prespecified visit windows and contain the canonical Energy Score, objective functional anchor, timestamps, and required completeness fields. Qualification describes analyzable longitudinal coverage and does not imply clinical change or causality.
• Longitudinal transition depth [Baseline through week 12]: Median and distribution of quality-qualified adjacent scheduled intervals per participant, plus the percentage of participants with at least four qualified intervals. Reasons for nonqualification will be summarized by prespecified category.
• Naturally occurring exposure-linked transition yield [Adjacent scheduled assessments from baseline through week 12]: Number and percentage of quality-qualified adjacent scheduled intervals containing a prospectively recorded participant-initiated, clinically directed, or otherwise naturally occurring change in a prespecified exposure category. The study assigns no treatment and does not interpret this measure as a causal treatment effect.
• Optional Flic symptom-event capture feasibility [From optional-module activation through week 12]: Among participants consenting to the optional Flic module: activated devices; active participant-weeks; event count and event days per participant-week; percentage of events received within 24 hours; and delayed, duplicate, unmapped, test, corrected, and failed-event rates. No minimum event count is required because absence of a press cannot be interpreted as absence of symptoms.
• Optional Flic confirmed intervention-marker yield [From optional-module activation through week 12]: Among Flic events mapped to an intervention: number and percentage followed by participant confirmation of intervention identity, occurrence, timing, and required exposure details; time to confirmation; and number linked to a quality-qualified adjacent assessment interval. Unconfirmed markers are not counted as intervention exposures, adherence, or perturbation-linked transitions.
• Optional Flic symptom-annotation completion [From optional-module activation through week 12]: Percentage of eligible Flic events with a completed requested follow-up annotation, median time from event to annotation, and distribution of participant-selected symptom or context labels. Analyses are descriptive and do not treat button events as validated symptom severity or clinical outcomes.

Sex: All, ages: 18 Years to any, accepts healthy volunteers

Inclusion Criteria:

* Age 18 years or older and able to provide legally effective informed consent.
* Located in a jurisdiction approved by the study team and applicable human-subjects oversight for remote participation.
* Meets the definition for one of seven prespecified cohorts: healthy comparison; broad mitochondrial disease (excluding participants assigned to the dedicated POLG cohort); POLG-related disease; ME/CFS, Long COVID, POTS, or a related post-infectious or autonomic illness; cancer, cancer survivorship, or treatment-related fatigue; Lyme disease or post-treatment Lyme disease syndrome; or another neuromuscular or persistent energy-limiting condition.
* Access to the required internet-capable device and ability to complete at least one approved home functional protocol.
* Willingness to complete baseline and repeated assessments for 12 weeks and to avoid intentional treatment changes solely for this study.

Exclusion Criteria:

* Any condition identified by the medical monitor that makes grip or sit-to-stand testing unsafe.
* Acute medical instability, recent hospitalization, or current symptoms requiring urgent evaluation.
* Inability to consent or follow the protocol without an approved legally authorized representative process.
* Planned participation in a conflicting interventional study during the observation window.
* No usable approved functional protocol after safety screening.

Participants meeting the dedicated POLG cohort definition are assigned to that cohort rather than the broad mitochondrial cohort. Final eligibility and cohort assignment are determined by qualified study personnel. Software may collect and flag screening information but does not make the final enrollment decision.

• Andrew Friedl, MS, MBA, Principal investigator, Precision Mito
• Deborah Manst, MD, Principal investigator, Precision Mito