{
  "name": "The Shape of Harm pilot estimand registry",
  "version": "0.2",
  "date": "2026-07-23",
  "status": "provisional_frozen_pending_content_review",
  "change_control": "Any change to population, exposure, comparator, outcome, intercurrent-event strategy, summary measure, geography, or time horizon creates a new version and requires a dated rationale.",
  "cross_scenario_rule": "The four pilot estimands are method-development anchors and must not be placed in one cross-substance rank. Cross-scenario comparison is allowed only inside a preregistered comparability class with compatible populations, settings, denominators, outcome definitions, and horizons.",
  "estimands": [
    {
      "estimand_id": "EST-AE-ALC-001",
      "version": "0.2",
      "status": "provisional_frozen_pending_content_review",
      "pilot_role": "acute community exposure anchor",
      "view": "one_episode",
      "scenario_id": "PILOT_A_ALC_60G_COMMUNITY",
      "substance": "Alcohol",
      "estimand_sentence": "Among U.S. adults aged 21–64 who drank alcohol in the past year, what is the 24-hour absolute risk of prespecified severe medical and behavioral outcomes after one community episode of consuming 60 g pure ethanol orally within 2 hours from regulated beverages, with no intentional co-use, compared with a matched non-drinking episode?",
      "target_population": "Community-dwelling U.S. adults aged 21–64 who drank alcohol at least once in the prior 12 months; primary analysis excludes known physiologic alcohol dependence and prespecified high-risk clinical subgroups are reported separately.",
      "exposure_strategy": "Consume 60 g pure ethanol orally from regulated beverage alcohol within a maximum 2-hour interval in a community/private setting; no intentional use of opioids, benzodiazepines, stimulants, or other intoxicants during the exposure window.",
      "comparator_strategy": "A matched 24-hour period in the same target population with no alcohol or other intoxicant exposure.",
      "outcome_set": "AE_MED_DEATH; AE_MED_ICU; AE_MED_HOSP; AE_BEH_USER; AE_BEH_VICTIM",
      "time_horizon": "0–24 hours from first drink",
      "intercurrent_events_strategy": "Emergency treatment and spontaneous cessation of drinking are retained under a treatment-policy strategy; intentional co-use is outside the primary estimand; unreported co-use is addressed in sensitivity analysis.",
      "summary_measure": "Age/sex-standardized absolute risk per 100,000 episodes; risk difference and risk ratio versus matched non-drinking periods; outcome-specific estimates remain separate.",
      "geography": "United States",
      "calendar_period": "2022–2025",
      "comparability_class": "AE_COMMUNITY_24H_MARKET_EXPOSURE",
      "primary_data_need": "A defensible denominator for drinking occasions linked or transportable to acute outcomes; survey-derived episode counts must match numerator population, geography, and period.",
      "identification_assumptions": "Accurate episode counting; adequate control of within-person time-varying confounding; outcome attribution within 24 hours; compatible numerator and denominator populations.",
      "feasibility": "medium-low",
      "prohibited_interpretation": "Not a risk estimate for alcohol dependence, chronic use, pregnancy, co-use, or consumption above/below 60 g; not directly comparable with controlled clinical administration scenarios."
    },
    {
      "estimand_id": "EST-RU-TOB-001",
      "version": "0.2",
      "status": "provisional_frozen_pending_content_review",
      "pilot_role": "chronic exposure and target-trial anchor",
      "view": "regular_use",
      "scenario_id": "PILOT_B_TOB_CONTINUE_VS_CEASE",
      "substance": "Tobacco cigarettes",
      "estimand_sentence": "Among U.S. adults aged 30–49 who currently smoke 10–30 regulated combustible cigarettes daily and have no prior major smoking-attributable disease, what is the 10-year difference in mortality and first major chronic physical-health events under sustained smoking of 20 cigarettes/day versus complete cigarette cessation at baseline?",
      "target_population": "U.S. adults aged 30–49 who smoke cigarettes daily at baseline, average 10–30 cigarettes/day, and have no prior myocardial infarction, stroke, COPD, or invasive cancer at baseline.",
      "exposure_strategy": "Sustain an average of 20 regulated combustible cigarettes/day for 10 years, with no other combustible tobacco products.",
      "comparator_strategy": "Complete cigarette cessation at baseline and no combustible tobacco use during follow-up; nicotine-replacement or approved cessation treatment is permitted and recorded.",
      "outcome_set": "All-cause death; first major cardiovascular event; incident COPD; invasive smoking-attributable cancer; CH_PHY health loss",
      "time_horizon": "10 years from baseline",
      "intercurrent_events_strategy": "Primary analysis is per-protocol: deviations from assigned smoking strategy are handled with prespecified censoring and inverse-probability weighting; death is a competing event for nonfatal outcomes.",
      "summary_measure": "Standardized 10-year cumulative incidence per 1,000 persons, risk difference, risk ratio, restricted mean survival difference, and DALYs per 1,000 persons where defensible.",
      "geography": "United States",
      "calendar_period": "Baseline cohorts 2010–2016 with follow-up through latest complete 10-year window",
      "comparability_class": "RU_CHRONIC_10Y_TARGET_TRIAL",
      "primary_data_need": "Longitudinal cohorts with repeated smoking intensity, cessation, confounders, and adjudicated mortality/morbidity; sufficient follow-up for latency-sensitive outcomes.",
      "identification_assumptions": "No unmeasured confounding after prespecified adjustment; positivity for cessation/continuation strategies; correct exposure measurement and censoring models; consistency of hypothetical strategies.",
      "feasibility": "medium-high for mortality/CVD; lower for cancer within 10 years",
      "prohibited_interpretation": "Not an intrinsic score for nicotine, all tobacco products, lifetime smoking, or initiation; the estimate is a continuation-versus-cessation contrast among baseline smokers."
    },
    {
      "estimand_id": "EST-AE-OPI-001",
      "version": "0.2",
      "status": "provisional_frozen_pending_content_review",
      "pilot_role": "illicit-supply and denominator stress test",
      "view": "one_episode",
      "scenario_id": "PILOT_C_OPIOID_UNVERIFIED_INTRNASAL",
      "substance": "Nonprescription opioids",
      "estimand_sentence": "Among U.S. adults aged 18–64 with current opioid tolerance, what is the 24-hour absolute risk of fatal or severe opioid toxicity after one intranasal community-use episode involving an unverified product sold as an opioid in the 2024 U.S. illicit market, with no intentional sedative or stimulant co-use?",
      "target_population": "U.S. adults aged 18–64 reporting nonprescription opioid use on at least 4 days/week in the prior 4 weeks and no abstinence interval longer than 72 hours; this is an operational proxy for current tolerance and must be validated.",
      "exposure_strategy": "One intranasal episode using a self-selected quantity of an unverified powder or pill sold as an opioid; chemical composition and potency are treated as market-distributed random variables and measured post hoc where drug-checking data exist.",
      "comparator_strategy": "A matched 24-hour period in the same target population without opioid use; secondary contrasts examine naloxone availability and verified versus unverified supply only if identification is defensible.",
      "outcome_set": "AE_MED_DEATH; respiratory depression requiring ventilation or naloxone; AE_MED_ICU; AE_MED_HOSP",
      "time_horizon": "0–24 hours from use",
      "intercurrent_events_strategy": "Naloxone, EMS response, and hospital treatment are retained as real-world rescue processes and separately modeled as modifiers; unintentional adulterants remain part of the supply estimand; intentional co-use is outside the primary estimand.",
      "summary_measure": "Absolute risk per 100,000 episodes, with the product-composition distribution integrated over the registered market and period; report route- and rescue-stratified estimates when possible.",
      "geography": "United States",
      "calendar_period": "Calendar year 2024; updated as a new scenario version for each market year",
      "comparability_class": "AE_COMMUNITY_24H_MARKET_EXPOSURE",
      "primary_data_need": "A valid episode denominator plus linked overdose outcomes and representative supply-composition data; death counts alone are insufficient.",
      "identification_assumptions": "Episode denominator represents the same population and market as outcomes; product composition distribution is representative; tolerance proxy is valid; rescue availability and co-use are measured sufficiently.",
      "feasibility": "low for absolute per-episode risk; high value as a stress test",
      "prohibited_interpretation": "Not molecule-specific fentanyl toxicity, not a fixed-dose estimate, not applicable after loss of tolerance, injection, intentional polysubstance use, supervised consumption, or a different market year."
    },
    {
      "estimand_id": "EST-AE-PSI-001",
      "version": "0.2",
      "status": "provisional_frozen_pending_content_review",
      "pilot_role": "controlled-administration safety anchor",
      "view": "one_episode",
      "scenario_id": "PILOT_D_PSI_25MG_CLINICAL",
      "substance": "Psilocybin",
      "estimand_sentence": "Among adults aged 21–65 with major depressive disorder who meet contemporary trial eligibility criteria, what is the 7-day risk difference in prespecified serious medical and severe psychiatric/behavioral outcomes after one 25 mg oral dose of synthetic psilocybin with preparation, continuous session monitoring, and post-session support versus placebo with identical support?",
      "target_population": "Adults aged 21–65 with major depressive disorder who satisfy the shared eligibility envelope of included controlled trials, including prespecified medical, psychiatric, medication, and family-history exclusions.",
      "exposure_strategy": "Single 25 mg oral dose of synthetic psilocybin in a clinical research setting after standardized preparation, with trained monitors present for the dosing session and standardized follow-up.",
      "comparator_strategy": "Placebo or inactive control with otherwise identical preparation, monitoring, and follow-up.",
      "outcome_set": "Serious adverse event; AE_MED_ICU; AE_MED_HOSP; severe anxiety/panic/psychotic event requiring rescue; self-harm or sustained clinically important worsening",
      "time_horizon": "Acute 0–24 hours and cumulative 0–7 days, reported separately",
      "intercurrent_events_strategy": "Rescue medication, extended observation, emergency transfer, and hospitalization are retained under a treatment-policy strategy and also counted in relevant outcomes; participants not dosed are excluded from the administration estimand.",
      "summary_measure": "Risk per 1,000 administrations and risk difference versus placebo, with exact or hierarchical binomial intervals; zero-event studies contribute information without being converted to zero risk.",
      "geography": "Countries and sites represented by eligible controlled trials; primary transport target United States/Canada",
      "calendar_period": "Trials conducted 2018–2026",
      "comparability_class": "AE_CONTROLLED_CLINICAL_7D",
      "primary_data_need": "Participant-level or arm-level controlled-trial safety data with harmonized adverse-event definitions and complete follow-up through 7 days.",
      "identification_assumptions": "Trial eligibility and support procedures are sufficiently harmonizable; adverse-event ascertainment is comparable; missing follow-up is ignorable or modeled; transport to target population is explicit.",
      "feasibility": "high within the controlled-clinical setting",
      "prohibited_interpretation": "Not applicable to unsupervised use, natural-mushroom products, other doses, people excluded from trials, polysubstance use, or long-term psychiatric outcomes."
    }
  ],
  "references": [
    {
      "id": "ICH-E9R1",
      "title": "E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis",
      "url": "https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e9r1-statistical-principles-clinical-trials-addendum-estimands-and-sensitivity-analysis-clinical"
    },
    {
      "id": "WHO-HED",
      "title": "WHO indicator metadata: heavy episodic drinking at least 60 g pure alcohol",
      "url": "https://www.who.int/data/gho/indicator-metadata-registry/imr-details/459"
    },
    {
      "id": "CDC-SMOKING-DEFS",
      "title": "CDC/NHIS adult tobacco-use definitions",
      "url": "https://archive.cdc.gov/www_cdc_gov/nchs/nhis/tobacco/tobacco_glossary.htm"
    },
    {
      "id": "CT-PSI-25MG",
      "title": "ClinicalTrials.gov example of single 25 mg oral psilocybin in a clinical setting",
      "url": "https://clinicaltrials.gov/study/NCT04620759"
    },
    {
      "id": "TARGET-TRIAL",
      "title": "Specifying the target trial for observational causal inference",
      "url": "https://www.ncbi.nlm.nih.gov/books/NBK547516/"
    }
  ]
}