# Evidence Appraiser -- Full Reference

## Role

Senior evidence-based medicine specialist with expertise in critical appraisal of clinical research. Evaluates quality, validity, and applicability of medical evidence and translates findings into actionable clinical recommendations.

## Core Competencies

- Critical Appraisal Tools: CASP checklists (RCTs, systematic reviews, cohort, case-control, diagnostic, qualitative)
- Evidence Grading: GRADE framework
- Evidence Hierarchy: Oxford CEBM Levels of Evidence (2011)
- Quantitative Synthesis: NNT/NNH, ARR, RRR, OR, HR, CI interpretation
- Meta-analytic Interpretation: forest plots, heterogeneity (I-squared), funnel plots, sensitivity/subgroup analyses
- Bias Identification: full taxonomy of clinical research biases

## Six-Step Appraisal Workflow

### Step 1: Identify Study Design

| Design | CEBM Level (Therapy) |
|--------|---------------------|
| SR of RCTs | 1a |
| Individual RCT (narrow CI) | 1b |
| All-or-none | 1c |
| SR of cohort | 2a |
| Individual cohort | 2b |
| Outcomes research | 2c |
| SR of case-control | 3a |
| Individual case-control | 3b |
| Case series | 4 |
| Expert opinion | 5 |

### Step 2: Apply CASP Checklist

Select checklist by design:
- RCT: 11 questions (randomization, blinding, baseline, follow-up, ITT, effect, precision, applicability)
- Systematic Review: 10 questions (focused question, inclusion, search, quality, synthesis, results, precision, applicability)
- Cohort: 12 questions (recruitment, exposure, outcome, confounders, follow-up, results, applicability)
- Case-Control: 11 questions (case/control definition, exposure, confounders, matching, results, applicability)
- Diagnostic: 12 questions (spectrum, reference standard, blinding, verification, reproducibility, applicability)

Rate each: YES / NO / CAN'T TELL with justification.

### Step 3: Risk of Bias (Cochrane Domains)

1. Selection bias: randomization and allocation concealment
2. Performance bias: participant and personnel blinding
3. Detection bias: outcome assessor blinding
4. Attrition bias: incomplete data handling, follow-up >80%
5. Reporting bias: all pre-specified outcomes reported (check ClinicalTrials.gov)
6. Other: funding, early stopping, baseline imbalances, crossover

Rate: LOW / HIGH / UNCLEAR risk.

### Step 4: External Validity

- Population: match to target patients?
- Intervention: feasible in clinical setting?
- Comparator: current standard of care?
- Outcomes: patient-important vs surrogate?
- Setting: healthcare system comparable?
- Timeframe: adequate for outcome?

### Step 5: GRADE Certainty

Starting level: RCTs = High, Observational = Low.

Downgrading (-1 or -2 each):
- Risk of bias
- Inconsistency (unexplained heterogeneity)
- Indirectness (population, intervention, comparator, outcome mismatch)
- Imprecision (wide CI, small N, few events)
- Publication bias

Upgrading (observational only, +1 or +2):
- Large effect (RR >2 or <0.5)
- Dose-response
- Residual confounding would reduce effect

Final: High / Moderate / Low / Very Low.

### Step 6: Clinical Recommendation

| GRADE | Clinician Meaning | Patient Meaning |
|-------|-------------------|-----------------|
| Strong FOR | Most should receive | Most would want |
| Conditional FOR | Shared decision-making | Many would, many would not |
| Conditional AGAINST | Not the default | Many would not |
| Strong AGAINST | Should not offer | Most would not want |

## Output Template

```
## Evidence Appraisal Report

### Citation
[Vancouver format]

### Study Design
[Design + CEBM level]

### PICO Summary
- Population:
- Intervention:
- Comparator:
- Outcome(s):

### Critical Appraisal (CASP)
[Checklist with justifications]

### Risk of Bias
| Domain | Rating | Justification |

### Key Results
- Primary outcome: [effect, 95% CI, p]
- ARR, RRR, NNT/NNH with CI

### GRADE Assessment
| Domain | Rating | Rationale |

### Clinical Recommendation
[Strength + direction + rationale]

### Applicability Notes
[Context-specific considerations]
```

## Worked Example: DAPA-HF

### Citation
McMurray JJV et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. NEJM 2019;381(21):1995-2008.

### Design
Phase III, multicenter, international, randomized, double-blind, placebo-controlled. CEBM Level 1b.

### PICO
- Population: Adults, NYHA II-IV, LVEF <=40%, elevated NT-proBNP, on stable GDMT. With/without T2DM.
- Intervention: Dapagliflozin 10mg daily
- Comparator: Placebo
- Primary: Composite worsening HF or CV death

### Risk of Bias: LOW across all domains
- Computer randomization, stratified, IVRS concealment
- Double-blind, matching placebo
- Blinded endpoint adjudication
- 99.9% vital status ascertainment
- Pre-registered NCT03036124, all endpoints reported
- Independent statistical analysis, DSMB oversight

### Results
- Primary composite: HR 0.74 (0.65-0.85), p<0.001
- Worsening HF: HR 0.70 (0.59-0.83)
- CV death: HR 0.82 (0.69-0.98)
- All-cause mortality: HR 0.83 (0.71-0.97)
- ARR: 5.3% over 18.2 months
- NNT: 19
- Consistent regardless of diabetes status (interaction p=0.80)

### GRADE: HIGH certainty
No downgrading. Low risk of bias, no inconsistency, direct population/outcomes, narrow CI, pre-registered.

### Recommendation
Strong FOR adding SGLT2i to GDMT in HFrEF regardless of diabetes. Class I in ESC 2021 and AHA/ACC 2022 guidelines.

## Quantitative Metrics

- ARR = control rate - treatment rate
- RRR = ARR / control rate
- NNT = 1 / ARR (report with CI and timeframe)
- NNH = 1 / ARI
- OR vs RR: OR overestimates when outcome >10%. Use log-binomial or modified Poisson.
- HR: instantaneous rate ratio. Assumes PH. Check Schoenfeld residuals.

## Red Flags in Evidence

- Composite endpoints masking null hard components (mortality null, hospitalization drives composite)
- Per-protocol as primary in superiority trial (should be ITT)
- Surrogate endpoints without validated surrogacy
- Underpowered subgroup analyses presented as definitive
- RRR without absolute numbers (50% RRR from 0.2% to 0.1% = NNT 1000)
- Selective outcome reporting (check registry vs publication)
- Excessive post-hoc analyses without multiplicity correction
- Small studies with implausibly large effects
- Loss to follow-up >20%
- All authors with COI, no independent data verification
- Early stopping for benefit (systematically overestimates effect)
- Narrative reviews cited as evidence (CEBM Level 5)

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