Mitochondrial DNA Copy Number as a Marker and Mediator of Stroke Prognosis
Bibliographic record
Abstract
<h3>Background and Objectives</h3> Low buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and poststroke mortality; however, its prognostic utility has not been extensively explored. Our goal was to investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of poststroke outcomes using epidemiologic and genetic studies. <h3>Methods</h3> First, we performed association testing between baseline buffy coat mtDNA-CN measurements and 1-month poststroke outcomes in 3,498 cases of acute, first stroke from 25 countries from the international, multicenter case-control study Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World (INTERSTROKE). Then, we performed 2-sample mendelian randomization analyses to evaluate potential causative effects of low mtDNA-CN on 3-month modified Rankin Scale (mRS) score. Genetic variants associated with mtDNA-CN levels were derived from the UK Biobank study (N = 383,476), and corresponding effects on 3-month mRS score were ascertained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME; N = 6,021) study. <h3>Results</h3> A 1-SD lower mtDNA-CN at baseline was associated with stroke severity (baseline mRS score: odds ratio [OR] 1.27, 95% confidence interval [CI] 1.19–1.36; <i>p</i> = 4.7 × 10<sup>−12</sup>). Independently of baseline stroke severity, lower mtDNA-CN was associated with increased odds of greater 1-month disability (ordinal mRS score: OR 1.16, 95% CI 1.08–1.24; <i>p</i> = 4.4 × 10<sup>−5</sup>), poor functional outcome status (mRS score 3–6 vs 0–2: OR 1.21, 95% CI 1.08–1.34; <i>p</i> = 6.9 × 10<sup>−4</sup>), and mortality (OR 1.35, 95% CI 1.14–1.59; <i>p</i> = 3.9 × 10<sup>−4</sup>). Subgroup analyses demonstrated consistent effects across stroke type, sex, age, country income level, and education level. In addition, mtDNA-CN significantly improved reclassification of poor functional outcome status (net reclassification index [NRI] score 0.16, 95% CI 0.08–0.23; <i>p</i> = 3.6 × 10<sup>−5</sup>) and mortality (NRI score 0.31, 95% CI 0.19–0.43; <i>p</i> = 1.7 × 10<sup>−7</sup>) beyond known prognosticators. With the use of independent datasets, mendelian randomization revealed that a 1-SD decrease in genetically determined mtDNA-CN was associated with increased odds of greater 3-month disability quantified by ordinal mRS score (OR 2.35, 95% CI 1.13–4.90; <i>p</i> = 0.02) and poor functional outcome status (OR 2.68, 95% CI 1.05–6.86; <i>p</i> = 0.04). <h3>Discussion</h3> Buffy coat mtDNA-CN is a novel and robust marker of poststroke prognosis that may also be a causal determinant of poststroke outcomes. <h3>Classification of Evidence</h3> This study provides Class II evidence that low buffy coat mtDNA-CN (>1 SD) was associated with worse baseline severity and 1-month outcomes in patients with ischemic or hemorrhagic stroke.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".