REVEAL III: Risk Evaluation and Education for Alzheimer's Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for REVEAL III: Risk Evaluation and Education for Alzheimer's Disease (NCT00462917), a randomized na study. The primary outcome is Center for Epidemiological Studies-Depression Scale (CES-D).

2. Clinical Question

REVEAL III examined how genetic-risk information was disclosed to healthy adults during an APOE-based assessment of Alzheimer’s disease risk. The interventions varied in the information content—Alzheimer’s disease risk information alone or that information plus incidental pleiotropic risk information—and in whether disclosure occurred in person or by telephone.

The clinical question is therefore about the study’s comparison structure and its intended psychological outcome, rather than a documented estimate of an intervention effect. The record describes what was measured and when, but it does not state a numerical contrast, confidence interval, or test result for the CES-D. It also does not report whether the primary question was framed as a comparison of information content, disclosure format, their combination, or changes across follow-up. Those details cannot be inferred from the factorial designation alone.

3. Trial Design

The registry record identifies REVEAL III as a randomized, single-masked, factorial study. It lists 290 participants enrolled and a completed status. The listed study start is 2007-03 and primary completion is 2009-10. The phase is recorded as NA. The sponsor is Brigham and Women’s Hospital.

Four behavioral intervention conditions are described. Participants received either Alzheimer’s disease risk information alone or that information plus incidental pleiotropic risk information. Each information condition was delivered either in person or by telephone during an APOE-based genetic risk assessment. This creates a factorial structure involving information content and disclosure format. The registry record does not report the allocation ratio, the exact randomization procedure, or which people or procedures were masked.

The primary outcome was the CES-D, with measurements scheduled at 6 weeks, 6 months, and 12 months post-disclosure. The record describes the scale as a 20-item measure of general depression, ranging from 0-60, with higher scores indicating greater general depression. The secondary outcome listed is the Impact of Events Scale (IES). The record lists 3 outcome measures but does not give numerical results for these outcomes in the registry record for this account.

Participant counts for the CES-D follow-up population are reported separately by time: 256 participants received genetic risk information and completed the 6-week follow-up, 252 provided data at 6 months, and 247 provided data at 12 months. These are outcome follow-up counts, not a statement that all randomized participants were analyzed under a particular intention-to-treat or per-protocol definition. That analysis-population definition is not reported in the registry record. The protocol, detailed statistical analysis plan, and sample-size justification are also 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: "Number of participants analyzed" are the number of participants who received genetic risk information and completed the 6-week follow-up (256). At 6 months, 252 participants provided data. At 12 months, 247 participants provided data.

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.

Population: Baseline population includes all participants who received genetic risk information, regardless of whether they completed follow-up time surveys.

6. Primary Endpoint

The registry lists the primary outcome as Center for Epidemiological Studies-Depression Scale (CES-D), measured over 6 weeks, 6 months, and 12 months post-disclosure.

The primary endpoint is the Center for Epidemiological Studies-Depression Scale (CES-D), a 20-item scale intended to measure general depression. Its scores range from 0-60, and higher scores indicate greater general depression. A scale score converts responses across several items into a quantitative measure, allowing the study to describe the distribution of scores and compare average scores across conditions or follow-up times when the relevant results are available.

The registry record identifies the CES-D as a mean outcome with standard deviation as its dispersion measure. The mean describes the average score in a group; the standard deviation describes how spread out individual scores are around that average. Both can help characterize an outcome, but neither alone indicates how precisely a difference between groups has been estimated.

Measurements were scheduled at 6 weeks, 6 months, and 12 months post-disclosure. Repeated measurement can describe whether scores change over follow-up and whether patterns differ across intervention conditions. Interpretation depends on the reported estimates, the analysis method, and the uncertainty around those estimates. The registry record does not report CES-D means, standard deviations, between-condition contrasts, confidence intervals, or p-values. It therefore does not establish the direction, size, or precision of any observed difference in this endpoint.

The CES-D is used as a continuous measure of general depression, not as a diagnosis. The registry description identifies what the score measures, but does not give a threshold for interpreting an individual score or a clinically important difference. Such thresholds are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a randomized factorial study with four behavioral conditions. In a factorial design, more than one intervention dimension is varied within the same study. General statistical interpretation can distinguish the effect associated with each dimension from a possible interaction between dimensions. An interaction means, in general, that the association of one dimension with the outcome may differ according to the level of another dimension. The registry record does not report which contrasts were prespecified, how the factorial structure was modeled, or any estimated effects.

What does a mean and standard deviation describe?

The CES-D is listed as a continuous outcome summarized by a mean and standard deviation. In general, the mean is the arithmetic average of scores in a group. The standard deviation describes the spread of scores around that mean. A mean gives a central summary, while the standard deviation gives information about participant-to-participant variability. Neither is itself a comparison between groups, and neither provides the uncertainty of a contrast. To assess a comparison, an analysis would ordinarily report an estimate of the contrast and a measure of its uncertainty, such as a confidence interval. Those numerical results are not reported in the registry record.

The score range is 0-60, with higher scores indicating greater general depression. Because the measure is continuous, analysis can retain variation across the scale rather than converting scores into categories. General statistical practice may use models suited to continuous outcomes, but the registry record does not identify the model, distributional assumptions, covariates, or estimation procedure used in this trial. No particular method should be attributed to the investigators based only on the outcome type.

How can follow-up at several times be interpreted?

The outcome timeframe includes 6 weeks, 6 months, and 12 months post-disclosure. Repeated measurements can be analyzed as separate time-specific outcomes or in a model that accounts for measurements from the same participant being related. These approaches answer different statistical questions and rely on different assumptions. The registry record does not report whether the time points were analyzed separately or jointly, how within-participant correlation was handled, or whether a time-by-condition interaction was assessed.

A time-specific group comparison describes conditions at one follow-up, while a longitudinal model can estimate patterns across follow-up. General interpretation of a longitudinal analysis requires knowing the model, its treatment of missing observations, and the estimand being targeted. None of those analysis details is reported in the registry record. The counts of participants with follow-up data are reported, but counts alone do not identify the analysis method or the source of missingness.

What does randomization contribute?

Random allocation is a design feature intended, in general, to make intervention groups comparable at the point of assignment, subject to how allocation was carried out and the number of participants. The record labels the study randomized but does not provide the allocation ratio or procedure. Randomization does not by itself guarantee that follow-up data are complete, that all analyses preserve the randomized comparison, or that an estimate is precise. Those judgments require information about the analysis population, missing data, and results.

The study is labelled single-masked. Masking can reduce some forms of bias when knowledge of assignment might influence measurement or behavior. The registry record does not say who was masked or how masking was implemented. Because the conditions involve different disclosure formats and content, the exact practical meaning of masking cannot be inferred from the label alone.

How should precision and significance be assessed?

General statistical interpretation separates the estimated effect from its precision. A confidence interval conveys uncertainty around an estimate under the model’s assumptions. A p-value, when reported, relates the observed data to a specified null hypothesis and analysis procedure; it does not state the probability that the null hypothesis is true. Neither type of result is reported for the CES-D in the registry record. The registry record also does not report an analysis plan, significance threshold, covariate adjustment, or interim analyses.

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Such a planning calculation is not observed power, and a sample-size illustration is not an outcome finding. The illustration describes the effect to detect as a stated fraction of the observed effect; the numerical effect and planning results are not included in the registry record for this explanation. The trial’s own sample-size justification is not reported in the registry record.

General statistical concepts can explain what the design and outcome summaries mean, but they cannot replace the missing analysis details. Without the actual estimates, uncertainty measures, and model description, the registry record does not permit an independent assessment of the size, precision, or statistical significance of the CES-D findings.

10. Multiplicity, Missing Data and Analysis Populations

The registry record identifies the CES-D as the primary outcome at 6 weeks, 6 months, and 12 months post-disclosure, and lists the Impact of Events Scale (IES) as a secondary outcome. It also lists 3 outcome measures. No numerical outcome analyses are reported in the registry record, and the record lists no analyses.

When several outcomes, time points, or contrasts are examined, the number of opportunities to find an apparently notable result can increase. General statistical approaches to multiplicity may include prespecifying a primary comparison, adjusting inference, or treating some analyses as exploratory. The registry record does not report a multiplicity strategy, a hierarchy of time points, or which comparisons were designated primary beyond identifying the CES-D as the primary outcome. It also does not report whether adjustment for multiple testing was planned or performed.

Follow-up counts are reported as 256 participants who received genetic risk information and completed the 6-week follow-up, 252 participants providing data at 6 months, and 247 at 12 months. The registry record does not explain the reasons for unavailable observations, whether missingness differed by condition, or whether the analysis used imputation, a complete-case approach, or another method. The analysis population beyond the stated follow-up counts is not reported in the registry record. Therefore, the effect of missing observations on the reported results cannot be evaluated.

The record does not report an intention-to-treat definition, per-protocol population, or sensitivity analyses for missing data. These omissions limit assessment of how closely any analysis might preserve the randomized comparison and how robust it might be to assumptions about missing outcomes.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death (1.6%).

The registry record lists serious and other adverse-event counts for each of the four disclosure conditions. For serious adverse events, the recorded counts are 1 among 64 at risk in the pleiotropic-information, in-person group; 0 among 70 in the Alzheimer’s-disease-only, telephone group; 0 among 55 in the pleiotropic-information, telephone group; and 0 among 68 in the Alzheimer’s-disease-only, in-person group. These are the counts stated in the registry record; they do not identify the event type for the participant with a serious event.

For other adverse events, the record lists 8 among 64 in the pleiotropic-information, in-person group, 9 among 70 in the Alzheimer’s-disease-only, telephone group, 4 among 55 in the pleiotropic-information, telephone group, and 5 among 68 in the Alzheimer’s-disease-only, in-person group. The record’s leading serious-event term is Death, 1.6%. It does not identify the relationship between that term and the group-level serious-event count in the registry record. The deaths field is not populated for the listed groups, so a group-specific death count is not reported in the registry record.

These adverse-event counts are descriptive. They are not adjusted comparisons, and the record does not provide confidence intervals, statistical tests, event timing, or attribution to an intervention. The number at risk shown for each group should be read with its corresponding event count; the counts alone do not establish whether groups differ. Serious and other adverse events are distinct categories in the registry record and should not be combined without an explicitly reported method.

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

The registry record establishes that REVEAL III was a randomized factorial study of behavioral genetic-risk disclosure in healthy adults. It describes four conditions that varied whether participants received Alzheimer’s disease risk information alone or additional incidental pleiotropic risk information, and whether disclosure took place in person or by telephone. It identifies the CES-D as the primary outcome and gives its measurement schedule and score description.

That information explains the question and structure of the trial, but it does not reveal the observed CES-D results. Numerical means, standard deviations, contrasts, confidence intervals, and p-values are not reported in the registry record. As a result, the record does not show whether scores differed by information content, disclosure format, or their combination, nor whether they changed across follow-up.

The absence of a reported result is not evidence that the interventions produced identical outcomes, and it is not evidence of a benefit or harm. A trial design specifies how comparisons might be made; it does not determine their findings. Participant follow-up counts and adverse-event counts also cannot substitute for outcome estimates or uncertainty measures.

The scale measures general depression as described in the registry, not a clinical diagnosis. The record does not give a clinically important difference or a decision threshold for interpreting score changes. Even if an estimate were available, assessing its practical meaning would require considering its magnitude, precision, measurement context, and an appropriate threshold. That threshold is not reported in the registry record.

Likewise, the adverse-event summaries are counts, not causal conclusions. The registry record does not report event attribution, adjusted comparisons, or uncertainty for those counts. The factual interpretation is therefore limited: the study’s design, outcomes, follow-up schedule, and certain adverse-event counts are described, while the primary outcome findings and their precision are not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable for combining two intervention dimensions in a factorial design: the content of genetic-risk information and the format of disclosure. Such a design can, in general, address more than a single pairwise comparison and can examine whether the association of one intervention dimension depends on another. That potential makes the planned contrasts and analysis model important to interpretation. The registry record does not report those details or their results.

The outcome was measured repeatedly after disclosure, at 6 weeks, 6 months, and 12 months. Repeated follow-up can distinguish a time-specific pattern from a pattern that develops or changes over time, provided the analysis and missing-data assumptions are described. The registry record supplies the measurement schedule and participant counts at each follow-up, but not the model used to analyze repeated observations or the outcome estimates.

The record also illustrates why design labels and outcome descriptions cannot stand in for results. Randomization and factorial allocation describe how a study was structured; the CES-D definition describes what was measured. Neither establishes the size or precision of a comparison. Without estimates and uncertainty measures, readers cannot assess whether the data support a distinction among disclosure conditions.

Finally, the study concerns communication of genetic-risk information, while its listed primary endpoint is a continuous depression-scale score. Keeping the measured endpoint distinct from broader interpretations is important: the record’s stated scale measures general depression, and the registry entries do not report a diagnosis, a clinical threshold, or a meaningful-change criterion. The trial’s statistical value to readers therefore lies in its clearly described comparison structure and follow-up framework, alongside the recognition that the registry record does not report the analyses needed to evaluate the primary outcome.

14. 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.

The most consequential limitation for interpreting the primary outcome is that the registry record does not report numerical CES-D findings. It gives the measure, score range, direction, dispersion type, and follow-up schedule, but not means, standard deviations, contrasts, confidence intervals, or p-values. The size and precision of any difference therefore cannot be assessed.

The design is labelled factorial, but the registry record does not specify the planned comparison structure, model, or interaction analysis. It also does not report the allocation ratio, randomization procedure, or who was masked. These omissions limit assessment of how the design was implemented and how its estimates were intended to be interpreted.

The reported follow-up counts are 256 at 6 weeks, 252 at 6 months, and 247 at 12 months. The registry record does not describe reasons for missing outcome data, their distribution across conditions, or the methods used to handle them. It does not define the analysis population beyond the stated count description. Missing-data assumptions and the robustness of results to those assumptions cannot be evaluated.

The registry record lists the IES as a secondary outcome and 3 outcome measures, but the registry entries do not include their numerical results or an approach to multiplicity. The detailed statistical analysis plan, sample-size justification, interim analyses, and clinical threshold for interpreting CES-D change are not reported in the registry record. These limitations are specific to what is documented for this trial and should not be replaced with assumptions about its protocol or analyses.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: REVEAL III: Risk Evaluation and Education for Alzheimer's Disease — NCT00462917.
• Registry record last updated 2018-10-23; status last verified 2018-09.
• Results first posted 2014-09-11.
• 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.

18. Record Summary

REVEAL III: Risk Evaluation and Education for Alzheimer’s Disease is listed as a completed, randomized, single-masked factorial study sponsored by Brigham and Women’s Hospital. The registry record lists 290 enrolled participants and a study start of 2007-03, with primary completion in 2009-10. The phase is recorded as NA.

The four behavioral conditions varied Alzheimer’s disease risk information alone versus that information plus incidental pleiotropic risk information, and in-person versus telephone disclosure. The primary outcome was the CES-D, assessed at 6 weeks, 6 months, and 12 months post-disclosure. The IES is listed as a secondary outcome.

The outcome description reports follow-up data counts of 256 at 6 weeks, 252 at 6 months, and 247 at 12 months. The registry record does not report numerical CES-D results, analyses, or a detailed statistical plan. It lists group-level serious and other adverse-event counts, but does not provide event attribution or inferential comparisons in the registry record.