Big data determination and validation of reference range for 24 hour urine cortisol by LCMS/MS
Bibliographic record
Abstract
OBJECTIVE: Twenty-four-hour urine-free cortisol (UFC) is a first-line test for Cushing syndrome (CS). A new mass spectrometry assay for UFC requires a validated, relevant reference range appropriate to a screening population. DESIGN: Combined retrospective and prospective cohort study in a government health system and tertiary endocrinology clinic, Canada. Participants were patients with potential features of CS. METHODS: The refineR reference interval algorithm was used to derive a middle 95%ile reference interval from 4830 UFC results in non-CS patients, compared with 120 prospective patients where evaluation excluded CS. RESULTS: Urine-free cortisol and 24-h urine volume were correlated (r = 0.28, P < .0001). There was no significant difference between the volume-corrected UFC distributions in the prospective vs retrospective populations (P = .09). Urine-free cortisol distribution was highly skewed (P < .0001) and showed strong sex interaction. The refineR-generated adult male UFC upper reference limit was 238 nmol/day (86.3 μg/day) and for females was 147 nmol/day (53.3 μg/day); urine volume-corrected, the upper limits were 89 nmol/L (32.3 μg/L) and 91 nmol/L (32.9 μg/L), respectively. Applied to both populations, between 3% and 8% of all results would be flagged high; most are expected to represent nonneoplastic (pseudo)Cushing's. CONCLUSIONS: We used mass population data, where the prevalence of CS was likely very rare, plus a carefully phenotyped sample where CS was considered but excluded, to derive a validated reference interval for 24-h UFC by mass spectrometry in populations that reflect real-world use of the test. Given the highly skewed upper tail of the population distribution, it is probable that high test specificity for CS will require multimodality diagnostic confirmation.
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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) | 0.000 | 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".