Quantifying Systematic Bias in Observational Causal Estimates Using Negative Controls: The Bias Attribution Fraction

@misc{zeng2026quantifying,
  title = {{Quantifying Systematic Bias in Observational Causal Estimates Using Negative Controls: The Bias Attribution Fraction}},
  author = {Z. Zeng and J. Wang and H. Zuo and L. Shu},
  howpublished = {medRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.08.26365019},
  url = {https://www.medrxiv.org/content/10.64898/2026.10.08.26365019v1},
  note = {CC BY},
}

TY  - UNPB
TI  - Quantifying Systematic Bias in Observational Causal Estimates Using Negative Controls: The Bias Attribution Fraction
AU  - Z. Zeng
AU  - J. Wang
AU  - H. Zuo
AU  - L. Shu
PY  - 2026
DA  - 2026/10/08
PB  - medRxiv
DO  - 10.64898/2026.10.08.26365019
UR  - https://www.medrxiv.org/content/10.64898/2026.10.08.26365019v1
AB  - ImportanceObservational studies dominate evidence in cardiovascular outcomes research, yet no widely adopted reporting standard requires authors to disclose how much of an observed association is attributable to systematic error. The negative-control calibration framework of the Observational Health Data Sciences and Informatics consortium returns a binary answer: a calibrated P-value either crosses 0.05 or it does not. That answer conflates "is there a signal" with "is the signal credible."  ObjectiveTo define the Bias Attribution Fraction (BAF), a continuous estimator in [0, 1] that quantifies the fraction of an observed log relative risk that is attributable to systematic bias, together with its 95% credible interval, and to evaluate whether reporting calibrated P-value plus BAF plus interval width produces more defensible decisions than reporting the calibrated P-value alone.  DesignThree-part study: (i) metric definition and interval construction; (ii) Monte Carlo simulation across 1920 conditions x 1000 repetitions = 1,920,000 simulated target estimates (a primary grid plus a sign-flipped companion grid of identical size, pooled for all analyses), with truth known by construction; (iii) two-arm beta-blocker target trial emulation in MIMIC IV, adhering to the TARGET guideline, with targeted maximum likelihood estimation (TMLE) and 12 negative-control outcomes.  SettingMIMIC IV (critical care) and MIMIC IV ECG, 2008 to 2019.  ParticipantsAdults with a first intensive care unit stay and a recorded 12-lead ECG.  ExposuresTwo clinical questions are evaluated: (1) reaching at least 50% of guideline-recommended target dose of an index beta-blocker within 7 days of admission, sustained to 12 months, versus lower or no exposure; (2) receiving guideline-directed medical therapy (GDMT) with at least two of three foundational drug classes at adequate dose for 12 months versus fewer.  Main Outcomes and MeasuresOne-year all-cause mortality. Primary analytic outputs: (i) the calibrated P-value from a negative-control empirical null distribution with 12 outcomes; (ii) BA[F] with a Markov chain Monte Carlo 95% credible interval; (iii) a verdict drawn from a truth-calibrated lookup table mapping the BA[F] x interval-width cell to a probability of being bias-dominated.  ResultsAcross 1,920,000 simulated repetitions, the calibrated P-value alone yielded a misuse rate (declared usable while truth was bias-dominated) of 36.02%. Adding the BAF point estimate reduced misuse to 16.48%, and requiring the whole credible interval of BAF to lie below 0.5, clear of the bias-dominated zone, reduced misuse to 10.16%. Requiring in addition a calibrated probability of bias dominance below 15% reduced misuse to 3.02% at the cost of declaring 22.1% of estimates usable (versus 61.8% for the calibrated P-value alone). Read from the bias-dominated view, meaning that withholding a repetition is a positive call and being truly bias-dominated is a positive truth, the BAF estimator achieved an area under the receiver operating characteristic curve of 0.922, compared with 0.787 for the calibrated P-value. In MIMIC IV, question 1 produced a calibrated P-value of 0.894 and BA[F] = 0.875 (95% credible interval 0.385 to 0.992); the apparent one-year mortality reduction of 16.9% was entirely attributable to systematic bias and the association was not usable as effect evidence. Question 2 also failed layer 1, with a calibrated P-value of 0.1026, and BA[F] = 0.460 placed it in the "competitive, no verdict" zone.  Conclusions and RelevancePairing the calibrated P-value with BAF and its 95% credible interval turns a binary credibility judgement into a three-channel report (signal existence, effect size, and bias fraction). Despite TARGET-adherent design, doubly robust TMLE, and 12 negative controls, both clinical questions in this study still failed to qualify as effect evidence, with question 1 demonstrating complete bias domination and BAF quantifying the systematic error that remained. The reporting standard proposed here can be applied to any observational study that includes negative controls, without requiring additional data.
ER  -