Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts (NCT04196374), a na na study. The primary outcome is Follow Through With Disclosure.

2. Clinical Question

3. Trial Design

This is a prospective cohort study of a genomic return-of-results process in the Framingham Heart Study and Jackson Heart Study. The registry lists the study as completed, with enrollment of 7603. The start date is 2021-06-09 and the primary completion date is 2025-05-30. The listed phase is NA, allocation is NA, masking is NONE, and the model is SINGLE GROUP. These registry classifications describe a study without randomized allocation or masking; they do not establish that participants were assigned to distinct comparison groups.

The project was intended to interpret genomic sequences from FHS and JHS participants previously sequenced by TOPMed who had consented to genomic return and/or genetic testing. For a participant with an actionable result in an ACMG v2.0 gene, the described process involved notification and an offer of clinical confirmation of the research result. The primary outcome focuses on follow-through with confirmation and disclosure to a health care provider among living participants whose result warranted verification.

Follow-through is not the only topic in the registry description. The listed secondary outcomes include guideline compliance, new and modified diagnoses, self-rated health, recommendations to referrals or services during clinical disclosure sessions, and health care utilization. The registry lists 15 outcome measures overall. It does not report how those outcomes were operationalized, the details of recruitment or consent procedures, or the extent to which participants completed each stage of disclosure and follow-up.

Because the study is single-group, it can describe what occurred within the return process if the relevant results are reported. It cannot, on the design information in the registry record alone, separate the effects of disclosure from other influences or establish what would have happened to comparable participants without the process. The registry lists zero analyses, and the primary outcome result is not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: FHS and JHS participants who had a disclosure session to discuss actionable genetic findings that were clinically confirmed.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Living JHS/FHS participants sequenced as part of the TOPMed program who were notified about an actionable genetic result that warranted having the research result verified.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Follow Through With Disclosure, measured over From genetic result notification to 8 months post-disclosure.

The primary endpoint is Follow Through With Disclosure, measured as a count of participants. It concerns living FHS and JHS participants sequenced through TOPMed who were notified about an actionable genetic result that warranted verification. A participant meets the described outcome when they follow through with having the research result confirmed and disclosed to their health care provider. The listed timeframe runs from genetic result notification to 8 months post-disclosure.

This endpoint is used to characterize a practical step in the return-of-results pathway: whether notification is followed by confirmation and communication with a health care provider. It is distinct from a measure of whether the genomic result is accurate, whether a diagnosis changes, or whether health outcomes improve. Those are separate questions, and the registry lists other outcomes related to diagnoses, guideline compliance, self-rated health, referrals or services, and health care utilization.

A participant count communicates how many people met the stated outcome, but its interpretation depends on knowing who was eligible and included in the denominator. The registry enrollment of 7603 is not specified as the primary endpoint denominator. The number notified, the number eligible for follow-through, the observed count, and any corresponding estimate of the proportion are not reported in the registry record. Without those details, the endpoint definition can be described, but the extent of follow-through cannot be quantified from the registry information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the outcome measure?

The primary outcome is a count of participants meeting a defined follow-through criterion. The criterion requires more than receiving a notification: the participant is described as following through with clinical confirmation of the research result and disclosure to their health care provider. This makes the endpoint a measure of completion within a care-related process. It is not a time-to-event endpoint as registered, and it is not described as a continuous measurement. The registry labels it as a binary outcome and specifies participants with an event as its meaning, while the endpoint parameter is a participant count.

Why does the denominator matter?

General statistical explanation: a count alone does not show how frequent an outcome was unless the relevant population size is also known. For this study, the eligible group is defined by living status, sequencing through TOPMed, notification of an actionable result, and a result warranting verification. The overall enrollment of 7603 is not reported as the number meeting those conditions. The registry record does not give the number notified or the number included in the primary endpoint analysis. As a result, a rate or proportion cannot be recovered from the information recorded here, and no rate should be inferred from enrollment.

What does uncertainty mean?

General statistical explanation: an estimate describes the data observed, while a confidence interval describes the range of values compatible with those data under the specified statistical method and assumptions. Its width reflects precision: a wider interval indicates more uncertainty about the underlying quantity. No primary outcome estimate or confidence interval is reported in the registry record, so precision cannot be evaluated. A statistical significance test would answer a different question from an interval and would not replace the need to understand the population, denominator, and endpoint definition.

What can a single-group design estimate?

General statistical explanation: a single-group cohort can describe outcomes among participants who receive or experience a process. A comparison intended to estimate a causal effect needs a credible counterfactual, often supported by randomization or by careful observational design and analysis. The registry record lists no randomized allocation and does not specify a like-for-like control group. Thus, even if a follow-through count were reported, it would describe observed participation in the process rather than establish the effect of the process compared with an alternative. No adjusted or comparative analysis is listed in the registry record.

How should the planning assumptions be understood?

The registry description of the planning illustration states that it uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. It also distinguishes total events for time-to-event illustrations from participants per arm for other illustrations. These are planning assumptions, not observed trial results. The study itself is registered as single-group, so the equal-allocation, two-arm illustration should not be read as the study's actual design. The observed effect and any resulting planning values are not reported in the registry record. General statistical explanation: planning calculations describe what sample size might be needed under stated assumptions; they do not demonstrate that an outcome effect exists, and they are not observed power.

Why can over-dispersion matter?

General statistical explanation: over-dispersion occurs when variation in the data is greater than a statistical model expects. If a count outcome is analyzed with a model that assumes less variability than the data actually contain, its standard errors may be too small and uncertainty may appear narrower than it is. Appropriate modeling depends on the distribution of the outcome, the sampling structure, and the analysis question. The registry describes the primary measure as a participant count and lists no dispersion value or analysis method. Over-dispersion is therefore a general methodological consideration, not a reported feature of this study's data.

What analyses are documented?

The registry lists zero analyses. It does not report a statistical analysis plan, a model for the primary outcome, adjustments for covariates, or a method for handling repeated observations or clustering within the FHS and JHS cohorts. It also does not report estimates, standard errors, confidence intervals, or p-values for follow-through. General statistical explanation: an analysis plan helps specify how endpoints, populations, missing observations, and multiplicity are handled before results are interpreted. Without those details, readers cannot determine whether a particular estimate would be adjusted, unadjusted, or based on a particular subset of participants.

What does the time window contribute?

The endpoint timeframe is stated as from genetic result notification to 8 months post-disclosure. It situates follow-through in relation to the notification and subsequent disclosure process. The registry does not explain how the timing was handled for participants who did not proceed to disclosure, how incomplete follow-up was classified, or whether all participants had the same opportunity for observation. Those details matter for interpreting a count because participants need an opportunity to meet the outcome, and the definition of the observation period determines which events can be counted.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("FHS & JHS Participants With an Actionable Genomic ")
n      <- c(71)
events <- c(48)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  FHS & JHS Participants With an Actionable Genomic   71  48  67.6  55.5  78.2  56.1  77.3  56.0  77.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures, including the primary follow-through outcome and secondary measures concerning guideline compliance, diagnoses, self-rated health, referrals or services, and health care utilization. It does not report a multiplicity strategy, such as a prespecified hierarchy of outcomes or an adjustment for testing multiple hypotheses. The record also lists zero analyses and does not identify which outcomes were analyzed or how any results would be interpreted jointly. General statistical explanation: examining multiple outcomes can increase the chance of finding at least one apparently notable result by chance. A prespecified analysis strategy helps readers understand whether and how that issue was addressed. No such strategy is reported in the registry record.

Missing-data procedures are also not reported in the registry record. The primary outcome depends on follow-through after notification and disclosure, but the record does not say how participants who could not be contacted, declined confirmation, had incomplete follow-up, or lacked information about disclosure were classified. It does not report the number with missing endpoint information or whether any sensitivity analyses were planned. These are not claims that data were missing; they are details absent from the registry record.

The analysis population is not reported in the registry record. The endpoint definition identifies living participants notified about a result warranting verification, but it does not state how many met that definition or how exclusions were handled. In particular, the total enrollment of 7603 cannot be assumed to be the denominator for follow-through. The registry record does not specify whether analyses used all eligible participants, only those with complete data, or another defined population. Without an analysis population, missing-data method, and multiplicity plan, the record does not allow a full assessment of the statistical handling of the outcomes.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The recorded safety figures are participant counts for the group titled FHS & JHS Participants With an Actionable Genomic Finding. The registry lists 71 participants at risk for serious adverse events and 0 affected. For other adverse events, it lists 71 at risk and 2 affected. Deaths are recorded as 0. The registry lists no top serious adverse-event terms.

These counts should be read as the safety information recorded for this group, not as a complete account of every possible safety outcome or as evidence about unlisted outcomes. The record does not provide event descriptions for the 2 participants with other adverse events, their severity or timing, or an explanation of how adverse events were collected. It also does not report a comparative safety analysis. Because this is a single-group study without a like-for-like control comparison, the counts do not establish whether an event was caused by result disclosure or by another factor.

General statistical explanation: a zero recorded count does not establish that the underlying risk is zero. How precisely a safety frequency can be estimated depends on the number observed, the population under surveillance, and the completeness and duration of follow-up. The registry record does not report a safety confidence interval or detailed follow-up information. The figures should therefore be described as recorded counts, without extending them into broader claims about safety.

13. What the Result Does, and Does Not, Mean

The registry record answers several design questions. It identifies a prospective, single-group cohort study involving the Framingham Heart Study and Jackson Heart Study, describes a return-of-results process for actionable genomic findings, and defines follow-through with confirmation and provider disclosure as the primary outcome. It also records enrollment of 7603, a completed status, and the study dates. These registry entries establish the context in which the outcome was intended to be assessed.

The record does not report the observed primary endpoint count, its denominator, an estimate of follow-through, or an uncertainty interval. It therefore does not show how often participants completed confirmation and disclosure. The overall enrollment cannot stand in for the narrower endpoint population, and no unreported result should be inferred from the endpoint definition or the study status.

Even with a reported count, the single-group design would support a description of follow-through among eligible participants, not a randomized estimate of what the process caused. The primary outcome is also a process measure. It does not by itself establish that a result led to a diagnosis, changed care, improved health, or affected costs. The registry lists outcomes related to some of those topics, but their results are not reported in the registry record.

The safety information records 0 serious adverse events among 71 at risk, 2 other adverse events among 71 at risk, and 0 deaths. These counts are limited to the categories and group recorded; details and comparative analyses are not reported. They should not be generalized beyond that information.

The appropriate interpretation is consequently bounded: the registry describes a study designed to examine the return of genomic results and defines a participant-level follow-through outcome, but it does not provide the primary result needed to quantify follow-through. Neither a beneficial nor an unfavorable conclusion about the outcome can be drawn from the registry information alone.

14. Why This Trial Matters Statistically

This study raises a statistical question that differs from a conventional comparison of assigned therapies. Its primary endpoint concerns whether participants move through a sequence of actions after an actionable genomic result is identified: notification, confirmation, and disclosure to a health care provider. Measuring follow-through can describe how a return process functions in practice. It can also help distinguish the availability of a result from completion of steps needed to confirm and communicate it.

The endpoint definition makes population specification especially important. The registry enrollment is 7603, whereas the primary population is living participants notified of an actionable finding that warranted verification. These groups should not be assumed to be identical. For a count to become an interpretable frequency, the number eligible and the number with outcome information are needed. Those details, along with the observed endpoint result, are not reported in the registry record.

The design also illustrates why descriptive and causal questions need to be kept separate. A single-group cohort can characterize what participants did within the study process. Without a like-for-like comparison, the same data cannot directly establish what would have happened under a different process. General statistical explanation: this distinction applies even when an outcome is measured carefully; the strength of measurement does not itself create a counterfactual comparison.

The registry lists a broad set of secondary outcomes spanning guidelines, diagnoses, health ratings, referrals or services, and health care use. Those topics reflect different kinds of questions and may require different outcome definitions and analyses. With 15 outcomes listed, a documented approach to prioritization and multiplicity would help readers interpret any collection of findings. Such an approach is not reported in the registry record, which lists zero analyses.

Statistically, the record is useful for understanding the intended population, process, endpoint, and limits of the design. Its value is constrained for estimating results because the primary count and analysis details are absent. The distinction between a well-defined question and a reported estimate is central: the former can be described, while the latter cannot be evaluated without outcome data and information about who contributed to the analysis.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations specific to this study follow from the registry information. First, the primary endpoint result is not reported in the registry record. There is no observed count, denominator, proportion, confidence interval, or test result with which to assess the frequency or precision of follow-through. The recorded enrollment of 7603 does not resolve this gap because it is not identified as the number of participants eligible for the primary endpoint.

Second, the primary population is defined through multiple conditions: participants must be living, sequenced through TOPMed, notified about an actionable result, and have a result warranting verification. The registry record does not report how many people met each condition or how the analysis population was formed. It also does not give details about incomplete notification, follow-up, confirmation, or disclosure. These omissions prevent assessment of selection into the endpoint population and the completeness of outcome ascertainment.

Third, the study is registered as single-group, with no randomized allocation or like-for-like control comparison. This design can describe observed process outcomes but does not, on its own, provide a controlled estimate of the effect of the return process. No adjustment strategy or comparative analysis is listed. The registry's planning illustration assumptions involving equal allocation between two arms should not be mistaken for the study design.

Fourth, the record lists 15 outcome measures but reports no multiplicity strategy, missing-data approach, analysis population, or statistical analysis plan. It lists zero analyses. The timing definition refers to the period from notification to 8 months post-disclosure, but procedures for participants who did not reach disclosure or had incomplete observation are not specified. Finally, the safety information is limited to participant counts and does not include event descriptions or comparative assessment. These are limitations of what the registry record documents; they do not establish that relevant analyses or procedures were absent from the conduct of the study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts — NCT04196374.
• Registry record last updated 2026-08-03; status last verified 2026-07.
• Results first posted 2026-08-03.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The record describes a completed prospective, single-group cohort study of genomic result return in the Framingham Heart Study and Jackson Heart Study. Enrollment is 7603. The study began on 2021-06-09 and has a primary completion date of 2025-05-30. Participants with an actionable genomic finding in an ACMG v2.0 gene were to be notified and offered clinical confirmation of the research result.

The primary outcome is a participant count for follow-through with confirmation and disclosure to a health care provider among living participants notified about an actionable result warranting verification. Its timeframe is from genetic result notification to 8 months post-disclosure. The observed primary result, denominator, analysis population, and statistical analysis plan are not reported in the registry record. The record lists 15 outcome measures and zero analyses.

Safety counts recorded for the actionable-finding group are 0 serious adverse events among 71 at risk, 2 other adverse events among 71 at risk, and 0 deaths. No top serious adverse-event terms are listed. The record supports a description of the study design and intended outcome, but does not report the primary result needed to quantify follow-through.