Please add imaging‑diagnosed cirrhosis as the primary endpoint and provide the revised full study template for a retrospective cohort of metabolic‑associated steatohepatitis patients in an obesity‑predominant community hospital.

Revised Study Template: Imaging-Diagnosed Cirrhosis as Primary Endpoint in MASH Patients

For a retrospective cohort study of metabolic-associated steatohepatitis (MASH) patients in an obesity-predominant community hospital setting, imaging-diagnosed cirrhosis should serve as the primary endpoint, with non-invasive elastography-based assessment (vibration-controlled transient elastography [VCTE] or MR elastography [MRE]) as the preferred diagnostic modality over morphologic imaging alone 1, 2.

Study Design Framework

Primary Endpoint Definition

Cirrhosis diagnosed by:

• VCTE with liver stiffness measurement ≥12.5 kPa (sensitivity 0.95, specificity 0.71-0.87 for MASLD populations) 3, 4
• MRE with cutoff ≥3.4-6.7 kPa (superior specificity to VCTE for ruling out cirrhosis in NAFLD/MASLD: 0.89 vs 0.72) 3
• Morphologic imaging features on CT/MRI as supportive criteria: surface nodularity, right lobe atrophy, caudate hypertrophy 5

Study Population Characteristics

Inclusion criteria should capture high-risk MASH patients:

• Adults with MASLD confirmed by imaging (hepatic steatosis on ultrasound, CT, or MRI)
• Obesity (BMI ≥30 kg/m² for non-Asians, ≥25 kg/m² for Asians) 1
• At least one additional cardiometabolic risk factor present 2

Key baseline variables to collect (these are the strongest predictors of cirrhosis progression per guidelines):

• Type 2 diabetes status and duration (strongest predictor: HR 1.69 for fibrosis progression, 4-fold increased HCC risk) 1
• Age >50 years (males) or postmenopausal status (women) 1
• Multiple cardiometabolic risk factors: hypertension, dyslipidemia, central adiposity 1
• Baseline ALT levels (>33 U/L males, >25 U/L females) 1
• Waist circumference (>94 cm men, >80 cm women for Caucasians) 1

Secondary Endpoints

Liver-related outcomes:

• Hepatic decompensation events (ascites, hepatic encephalopathy, variceal bleeding) 1
• Hepatocellular carcinoma development 1
• Liver-related mortality 1

Cardiometabolic outcomes:

• Major adverse cardiovascular events (acute coronary syndrome, stroke) 6
• Progression of metabolic comorbidities 1

Diagnostic Approach Algorithm

Step 1: Initial risk stratification

• Calculate FIB-4 score at baseline 2
• Obtain baseline imaging for steatosis confirmation

Step 2: Elastography assessment

• Primary method: VCTE (point-of-care, cost-effective) with cutoff ≥12.5 kPa for cirrhosis 3, 4
• Alternative: MRE if VCTE fails (obesity, ascites) or for superior specificity in ruling out cirrhosis 3
• Document failure rates and reasons (critical for intention-to-diagnose analysis) 3, 4

Step 3: Confirmatory assessment

• Morphologic CT/MRI features to support elastography findings 5
• Consider liver biopsy only for discordant results or clinical trial enrollment 7

Critical Methodological Considerations

Avoid common pitfalls:

• Do NOT exclude obese patients (BMI >30 kg/m²) from VCTE analysis—this introduces unacceptable bias 4
• Perform intention-to-diagnose analysis, not per-protocol analysis that excludes failed measurements 3, 4
• Document all unsuccessful elastography attempts with reasons (obesity, ascites, operator experience) 3

For obesity-predominant populations specifically:

• Expect higher VCTE failure rates (up to 20-30% in severe obesity) 3, 4
• MRE may be necessary in 15-25% of patients 3
• Consider clinical obesity criteria (anthropometric + clinical) rather than BMI alone—identifies 20.6% vs 8.1% with advanced fibrosis 6

Sample Size and Follow-up

Based on cirrhosis prevalence in obesity-MASH populations:

• Expect 12-30% baseline cirrhosis prevalence in obesity-predominant MASH cohorts 6, 8
• Plan for 5-10 year follow-up to capture progression events (cirrhosis incidence 29.75-90.44 per 1,000 person-years) 7
• Account for competing cardiovascular mortality risk 1

Data Collection Template

Baseline assessment:

• Demographics: age, sex, ethnicity (Hispanic ethnicity increases risk) 1
• Anthropometrics: BMI, waist circumference, visceral fat assessment if available 6
• Metabolic profile: T2D duration, HbA1c, insulin resistance markers, lipid panel 1
• Liver enzymes: ALT, AST, platelet count 1
• Elastography: VCTE/MRE values, quality metrics (IQR/median ratio for VCTE) 3
• Imaging: steatosis grade, morphologic cirrhosis features 5, 6

Follow-up assessments (annual minimum):

• Repeat elastography to assess progression 2
• Clinical decompensation events 1
• HCC surveillance (ultrasound ± AFP every 6 months if cirrhotic) 5
• Cardiovascular events 6
• All-cause and liver-related mortality 1

Statistical Analysis Plan

Primary analysis:

• Cumulative incidence of imaging-diagnosed cirrhosis at 5 and 10 years
• Cox proportional hazards for time-to-cirrhosis, adjusting for T2D, age, obesity severity, baseline fibrosis stage 1

Subgroup analyses:

• Stratify by T2D status (present vs absent) 1
• Stratify by number of cardiometabolic risk factors (1 vs ≥2) 1
• Age/sex subgroups (>50 males, postmenopausal women) 1

Sensitivity analyses:

• Compare VCTE vs MRE diagnostic concordance 3
• Intention-to-diagnose vs per-protocol analysis 3, 4
• Validate against liver biopsy subset if available 7, 8

This template prioritizes the most clinically meaningful endpoint—cirrhosis—which is the strongest predictor of liver-related mortality (25.6/1,000 person-years in MASH) and drives clinical decision-making for HCC surveillance, transplant evaluation, and therapeutic interventions 1, 2.