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Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001)

LevelTherapy/Prevention, Aetiology/HarmPrognosisDiagnosisDifferential diagnosis/symptom prevalence studyEconomic and decision analyses
  • Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.

  • Notes

  • Users can add a minus-sign “-” to denote the level of that fails to provide a conclusive answer because of:

  • • EITHER a single result with a wide Confidence Interval (such that, for example, an ARR in an RCT is not statistically significant but whose confidence intervals fail to exclude clinically important benefit or harm)

  • • OR a Systematic Review with troublesome (and statistically significant) heterogeneity.

  • • Such evidence is inconclusive, and therefore can only generate Grade D recommendations.

  • *

    By homogeneity we mean a systematic review that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all systematic reviews with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a “-” at the end of their designated level.

  • Clinical Decision Rule. (These are algorithms or scoring systems which lead to a prognostic estimation or a diagnostic category.)

  • See note ♯2 for advice on how to understand, rate and use trials or other studies with wide confidence intervals.

  • §

    Met when all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but none now die on it.

  • §§

    By poor quality cohort study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. By poor quality case-control study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both cases and controls and/or failed to identify or appropriately control known confounders.

  • §§§

    Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into “derivation” and “validation” samples.

  • ††

    An “Absolute SpPin” is a diagnostic finding whose Specificity is so high that a Positive result rules-in the diagnosis. An “Absolute SnNout” is a diagnostic finding whose Sensitivity is so high that a Negative result rules-out the diagnosis.

  • †††

    Good reference standards are independent of the test, and applied blindly or objectively to applied to all patients. Poor reference standards are haphazardly applied, but still independent of the test. Use of a non-independent reference standard (where the ‘test’ is included in the ‘reference’, or where the ‘testing’ affects the ‘reference’) implies a level 4 study.

  • ††††

    Better-value treatments are clearly as good but cheaper, or better at the same or reduced cost. Worse-value treatments are as good and more expensive, or worse and the equally or more expensive.

  • **

    Validating studies test the quality of a specific diagnostic test, based on prior evidence. An exploratory study collects information and trawls the data (e.g. using a regression analysis) to find which factors are ‘significant’.

  • ***

    By poor quality prognostic cohort study we mean one in which sampling was biased in favour of patients who already had the target outcome, or the measurement of outcomes was accomplished in <80% of study patients, or outcomes were determined in an unblinded, non-objective way, or there was no correction for confounding factors.

  • ****

    Good follow-up in a differential diagnosis study is >80%, with adequate time for alternative diagnoses to emerge (eg 1-6 months acute, 1–5 years chronic)

1aSR (with homogeneity*) of RCTsSR (with homogeneity*) of inception cohort studies; CDR validated in different populationsSR (with homogeneity*) of Level 1 diagnostic studies; CDR with 1b studies from different clinical centresSR (with homogeneity*) of prospective cohort studiesSR (with homogeneity*) of Level 1 economic studies
1bIndividual RCT (with narrow Confidence Interval)Individual inception cohort study with > 80% follow-up; CDR validated in a single populationValidating** cohort study with good††† reference standards; or CDR tested within one clinical centreProspective cohort study with good follow-up****Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses
1cAll or none§All or none case-seriesAbsolute SpPins and SnNouts††All or none case-seriesAbsolute better-value or worse-value analyses††††
2aSR (with homogeneity*) of cohort studiesSR (with homogeneity*) of either retrospective cohort studies or untreated control groups in RCTsSR (with homogeneity*) of Level >2 diagnostic studiesSR (with homogeneity*) of 2b and better studiesSR (with homogeneity*) of Level >2 economic studies
2bIndividual cohort study (including low quality RCT; e.g., <80% follow-up)Retrospective cohort study or follow-up of untreated control patients in an RCT; Derivation of CDR or validated on split-sample§§§ onlyExploratory** cohort study with good†††reference standards; CDR after derivation, or validated only on split-sample§§§ or databasesRetrospective cohort study, or poor follow-upAnalysis based on clinically sensible costs or alternatives; limited review(s) of the evidence, or single studies; and including multi-way sensitivity analyses
2c“Outcomes” Research; Ecological studies“Outcomes” Research Ecological studiesAudit or outcomes research
3aSR (with homogeneity*) of case-control studies SR (with homogeneity*) of 3b and better studiesSR (with homogeneity*) of 3b and better studiesSR (with homogeneity*) of 3b and better studies
3bIndividual Case-Control Study Non-consecutive study; or without consistently applied reference standardsNon-consecutive cohort study, or very limited populationAnalysis based on limited alternatives or costs, poor quality estimates of data, but including sensitivity analyses incorporating clinically sensible variations.
4Case-series (and poor quality cohort and case-control studies§§)Case-series (and poor quality prognostic cohort studies***)Case-control study, poor or non-independent reference standardCase-series or superseded reference standardsAnalysis with no sensitivity analysis
5Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”Expert opinion without explicit critical appraisal, or based on economic theory or “first principles”

Grades of Recommendation

  1. “Extrapolations” are where data is used in a situation which has potentially clinically important differences than the original study situation.

Aconsistent level 1 studies
Bconsistent level 2 or 3 studies or extrapolations from level 1 studies
Clevel 4 studies or extrapolations from level 2 or 3 studies
Dlevel 5 evidence or troublingly inconsistent or inconclusive studies of any level

Permission received from the Oxford Centre for Evidence-based Medicine to reproduce Levels of Evidence Model. Levels of Evidence produced by Bob Phillips, Chris Ball, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes.