Low Low-Density Lipoprotein Levels Are Associated With, But Do Not Causally Contribute to, Increased Mortality in Sepsis*
Bibliographic record
Abstract
OBJECTIVES: Low low-density lipoprotein levels are associated with increased mortality in sepsis. Whether low low-density lipoprotein levels contribute causally to adverse sepsis outcome is unknown. DESIGN: Retrospective analysis of two sepsis patient cohorts using a Mendelian Randomization strategy. SETTING: Sepsis patients enrolled into clinical research cohorts at tertiary care teaching hospitals. PATIENTS: The first cohort included 200 sepsis patients enrolled in an observational study in a hospital Emergency Department. The second cohort included genotyped patients enrolled in the Vasopressin and Septic Shock Trial. INTERVENTIONS: Retrospective analysis of these patient datasets. In 632 patients enrolled in Vasopressin and Septic Shock Trial, Proprotein Convertase Subtilisin/Kexin type 9, and 3-Hydroxy-3-Methylglutaryl-CoA Reductase single nucleotide polymorphisms known to be associated with low-density lipoprotein levels were genotyped, and a genetic score related to low-density lipoprotein levels was calculated. MEASUREMENTS AND MAIN RESULTS: In the first cohort, we replicated the finding that low low-density lipoprotein levels are associated with increased 28-day mortality. In genotyped patients in the Vasopressin and Septic Shock Trial trial, we found that the 3-Hydroxy-3-Methylglutaryl-CoA Reductase genetic score, known to be directly related to low low-density lipoprotein levels, was not associated with increased mortality. Surprisingly the Proprotein Convertase Subtilisin/Kexin type 9 genetic score, known to be directly related to low low-density lipoprotein levels, was associated with decreased (not increased) mortality. CONCLUSIONS: Both 3-Hydroxy-3-Methylglutaryl-CoA Reductase and Proprotein Convertase Subtilisin/Kexin type 9 genetic scores should have been associated with increased mortality if low low-density lipoprotein levels contributed causally to sepsis mortality. But this was not the case, and the opposite was observed for the Proprotein Convertase Subtilisin/Kexin type 9 genetic score. This suggests that low-density lipoprotein levels, per se, do not contribute causally to adverse sepsis outcomes. The Proprotein Convertase Subtilisin/Kexin type 9 genetic score finding raises the possibility that increased low-density lipoprotein clearance (the effect of these Proprotein Convertase Subtilisin/Kexin type 9 genotypes) may contribute to improved sepsis outcomes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.007 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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 source (direct Gemma or distilled Codex), 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".