Repeatability in Hyperpolarized 3-Helium With MRI: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Repeatability in Hyperpolarized 3-Helium With MRI (NCT03776747), a non-randomized phase 4 study. The primary outcome is Apparent Diffusion Coefficient (ADC) as a Function of Lung Inflation Levels..

2. Clinical Question

The study asks whether apparent diffusion coefficient (ADC) measured with hyperpolarized 3-Helium MRI varies with lung inflation, and whether its intrinsic variability can be characterized to support standardization of the biomarker for future pulmonary pathology assessments. The registry describes a study in healthy adult subjects and identifies the primary measurement as ADC at different levels of vital capacity.

This is a measurement-focused question, not a comparison of clinical treatments. The registry frames the work as an assessment of reproducibility and results of hyperpolarized 3-Helium gas as an MRI contrast agent. However, it does not report numerical ADC estimates, variability estimates, or a result describing whether measurements differed across inflation levels. The posted record therefore defines the intended comparison but does not establish its observed magnitude or precision.

3. Trial Design

The registry identifies this as a Phase 4 study with nonrandomized allocation, no masking, and a single-group model. Its status is completed. Enrollment is listed as 18. The study began on 2008-07-22, and primary completion is recorded as 2012-06. The sponsor is Eric A. Hoffman.

The study description centers on healthy adult subjects and on the reproducibility of hyperpolarized 3-Helium gas MRI of the lungs. Listed procedures include vitals, pulmonary function tests, an initial protocol MRI scan, a prone hyperpolarized 3-Helium gas scan, and a supine hyperpolarized 3-Helium gas scan. The arm descriptions distinguish a prone scan group from a supine scan group. Those descriptions do not make the arms randomized, masked, or equivalent in the way a controlled parallel-group trial might be.

The primary outcome description narrows the analysis population and comparison: it says only supine MRI scans were performed for the ADC comparison, and that values at 20%, 60% and 100% vital capacity were compared against each other. Thus, the primary question is framed as a comparison of measurements across inflation levels, rather than as a treatment contrast between the prone and supine groups. The record does not explain how the stated arm descriptions relate to that primary-outcome population.

The listed timeframe is through study completion, with measurements completed at one day visit only. The registry does not report visit-by-visit timing beyond that statement, the order of measurements, or whether scans were repeated at each inflation level. It also does not report the rationale for enrollment, a sample-size justification, an interim analysis plan, or the detailed statistical analysis plan. These omissions limit assessment of how the intended measurement-reproducibility question was translated into the analysis.

Because allocation is nonrandomized and the study model is single-group, the arm labels should not be read as evidence of a randomized head-to-head comparison. In particular, the registry does not establish that prone and supine scans form like-for-like control groups for the primary endpoint. The stated primary comparison instead concerns ADC values across vital-capacity levels in the supine measurements.

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: Only Supine MRI's were performed. ADC values at 20%, 60% and 100% vital capacity (VC) were compared against each other.

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: Only supine MRI subjects were recruited

6. Primary Endpoint

The registry lists the primary outcome as Apparent Diffusion Coefficient (ADC) as a Function of Lung Inflation Levels., measured over Through study completion, measurements completed at one day visit only..

The primary endpoint is mean apparent diffusion coefficient (ADC), reported in ADC (cm2/sec), as a function of lung inflation levels. ADC is a quantitative MRI measure used in this study as a biomarker of lung structure and gas diffusion. The registry's stated purpose is to validate its intrinsic variability as normal procedural and physiological conditions change, with the longer-term aim of standardizing its use in future assessments of pulmonary pathologies.

The primary outcome description specifies measurements at 20%, 60% and 100% vital capacity (VC), compared against one another, and states that only supine MRI scans were performed for this comparison. The outcome is continuous, and the registry identifies the summary parameter as a mean with standard deviation. In general, a mean describes the central value of a continuous measurement, while a standard deviation describes the spread of measurements around that mean. Both are relevant to a reproducibility question: the mean indicates the measurement level, while variability indicates how much measurements differ within the observed conditions.

The record gives the endpoint definition and unit but does not report the mean ADC values or standard deviations at any of the stated inflation levels. It also does not report a numerical contrast, confidence interval, or test result for comparisons across levels. As a result, the endpoint's intended meaning is clear, but its observed values and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Interpreting a measurement study requires separating the clinical or physiological question from the statistical summary used to address it. Here, the question concerns ADC measured by hyperpolarized 3-Helium MRI at different lung inflation levels. The endpoint is continuous, and the registry names the mean and standard deviation as the summary measures. The record does not describe the inferential method used to compare those measurements.

What does the mean describe?

In general, a mean is a measure of the center of a set of continuous observations. If measurements are made under several conditions, condition-specific means can describe the average ADC at each condition. Comparing those averages can help characterize a systematic change associated with the measurement condition. A mean alone does not show how much individual measurements vary, whether the observations are clustered within participants, or how uncertain the estimated average is.

The registry identifies the ADC outcome as a mean but does not give the condition-specific values. It therefore does not allow a reader to determine the direction or size of any average change across the stated vital-capacity levels. No effect estimate is reported, and one should not infer a numerical contrast from the endpoint definition alone.

Why is the standard deviation relevant?

In general, a standard deviation describes the spread of observations around their mean. For a measurement-reproducibility question, spread can be informative because it indicates how much individual observed values vary in the studied conditions. It is not interchangeable with a standard error or a confidence interval: those quantities describe uncertainty in an estimated summary rather than the dispersion of individual observations.

The registry names standard deviation as the endpoint dispersion measure, but the values are not reported. It also does not specify whether the reported spread is calculated across participants, repeated scans, or another observational unit. Without that information, the intended summary is known but the precise interpretation of variability cannot be fully assessed.

What would a confidence interval add?

In general, a confidence interval presents a range of values compatible with an estimate under the assumptions of the statistical method. For a difference in ADC between inflation levels, it would help show both the estimated contrast and its precision. A narrow interval indicates greater precision than a wide interval, although the interval's meaning depends on the analysis design and assumptions. A confidence interval is not a guarantee that the true value lies within the reported range.

No confidence interval for ADC or for a contrast between inflation levels is reported in the registry record. There is therefore no basis to assess statistical precision from interval estimates. A reader also cannot determine whether any potential difference is compatible with both negligible and substantial changes.

How does the measurement structure affect analysis?

In general, measurements taken from the same participant under multiple conditions are correlated. Treating correlated observations as independent can misstate uncertainty, because measurements from one participant may share characteristics. Analyses for repeated or paired measurements account for this dependence, whereas methods for independent groups use a different structure. The appropriate approach depends on how measurements were collected, their ordering, and the intended estimand.

The primary outcome description compares multiple vital-capacity levels in supine MRI, which suggests a condition-based measurement question. However, the registry does not say whether each participant contributed measurements at every level, whether repeated scans were taken, or whether observations were analyzed as paired, repeated, or independent. The statistical method is not reported, so it is not possible to verify how the within-participant structure was handled.

What does over-dispersion mean in general?

Over-dispersion is a general concern when observed variability exceeds what a statistical model assumes. It is especially discussed for count outcomes, where an overly restrictive variance assumption can make uncertainty appear too small. For a continuous ADC endpoint, the more immediate questions are how the distribution was characterized, whether variability differed across conditions, and whether the analysis accounted for repeated measurements. The registry does not describe model diagnostics or variance assumptions. No conclusion about over-dispersion can be drawn from the record.

How should the planning illustration be read?

The planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with an effect defined as a stated fraction of the observed effect. For non-time-to-event outcomes, the planning output is expressed as participants per arm for 80% power or other stated planning levels. These are planning illustrations based on an observed effect, not observed power and not evidence about the trial's original design.

Those assumptions describe a two-arm planning framework, while the registry's primary endpoint describes comparisons among inflation levels in supine scans and lists a single-group model. The registry does not report an observed ADC effect estimate from which to evaluate such a planning illustration, nor does it say that these assumptions were used to design the study. Accordingly, the planning framework should not be mistaken for the study's analysis plan or for a justification of its enrollment.

More broadly, a statistical method is only interpretable when the estimand, measurement structure, analysis population, and uncertainty summary are clear. The registry supplies the endpoint concept and a limited description of measurement conditions, but not the numerical results or analysis details. General statistical principles can clarify what would be needed; they cannot substitute for the missing endpoint estimates.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and one analysis. It does not report a multiplicity adjustment, a hierarchy of endpoints, or a plan for handling multiple comparisons. The primary endpoint itself identifies ADC measurements at 20%, 60% and 100% vital capacity as comparisons against one another. When several contrasts are considered, multiplicity can matter because the chance of at least one misleadingly extreme result may increase. In general, the approach depends on whether the comparisons were prespecified and which contrast is the main scientific target. The record does not describe such decisions or report adjusted or unadjusted tests.

Missing-data handling is not reported in the registry record. The record does not state how many participants contributed ADC measurements at each inflation level, whether any measurements were unavailable, or how incomplete sets of measurements were treated. It also does not report an imputation method, a sensitivity analysis, or assumptions about why data might be missing. Without those details, completeness of the primary endpoint and the influence of missing observations cannot be assessed.

The analysis population is also not defined beyond the statement that only supine MRI scans were performed for the primary comparison. There is no reported distinction between enrolled, eligible, completed, or analyzed participants for the ADC endpoint. The registry's enrollment entry is 18, but that does not establish the endpoint-specific analysis count. The record also does not state whether all participants completed the same set of procedures or whether the primary analysis included every available measurement.

These omissions do not establish that the study had missing observations or that multiplicity was mishandled. They mean that the registry record does not report the information needed to evaluate those issues. Interpretation of any numerical estimates would require clear reporting of the analysis population, available measurements, comparison plan, and treatment of missing data.

11. 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.

The adverse-event record lists zero serious adverse events, zero other adverse events, and zero deaths for the supine MRI group, with 18 participants at risk recorded for that group. For the prone MRI group, the record lists zero participants at risk and zero counts for serious adverse events, other adverse events, and deaths. No serious adverse-event terms are listed.

The zero at-risk entry for the prone group should not be read as a zero-event finding among a known group of participants. The registry does not explain why no participants are recorded at risk for that group, or how that entry relates to the prone arm description. The record also does not report the adverse-event collection period, surveillance procedures, or criteria used to classify events.

In general, a zero count in a registry entry means that no events are recorded for that category and risk set; it does not prove that an event was impossible or that all relevant harms were captured. These figures are descriptive and should be interpreted within the limits of the reported risk sets and reporting details. The record does not provide further information to assess safety ascertainment.

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

The study's stated purpose is to examine reproducibility and measurement variability for hyperpolarized 3-Helium gas MRI of the lungs. It defines ADC as the primary continuous outcome and identifies vital-capacity levels for the supine scan comparison. These features make the study a measurement-focused investigation rather than a test of a treatment effect.

What the registry record does establish is the intended measurement question: whether ADC varies with lung inflation under the stated scan conditions, and whether characterizing that variability may help standardize a biomarker for future pulmonary pathology assessments. The record also gives the study model, allocation description, enrollment entry, and planned measurement context.

What it does not establish is the observed ADC pattern. Numerical means, standard deviations, contrasts, confidence intervals, and test results are not reported. The record therefore cannot support a conclusion about the magnitude, direction, or precision of changes in ADC across the inflation levels. It also cannot demonstrate reproducibility quantitatively, because the information needed to evaluate repeat-measurement agreement or variability is not reported.

The study's single-group, nonrandomized design should not be recast as a randomized comparison of prone versus supine scanning. The primary outcome description specifies comparisons among inflation levels in supine measurements, while the record does not explain the relation between that analysis and the separate prone and supine arm descriptions. A treatment-like conclusion about one position being better than another would go beyond the stated primary question and the reported information.

Nor does the enrollment entry alone show how many participants contributed usable data to each endpoint condition. The analysis population and missing-data approach are not reported. The meaning of any putative average must therefore remain bounded by the record's stated aims and reporting gaps. In short, the registry describes a study designed to investigate ADC variability, but does not report the numerical primary findings required to judge that variability or its precision.

13. Why This Trial Matters Statistically

Clinical biomarkers are useful only when their measurements can be interpreted consistently. A scan-derived quantity may vary with physiology or procedure as well as with the disease process of interest. The registry identifies this issue directly: it proposes to assess the intrinsic variability of ADC as a function of lung inflation, with a goal of standardizing future use of the biomarker in pulmonary pathology assessments.

That makes the study statistically relevant even though the registry does not report numerical endpoint results. It highlights that measurement conditions are part of the estimand: an ADC value at one inflation level is not automatically interchangeable with a value taken under another condition. Comparing stated vital-capacity levels is one way to investigate whether the measurement depends on lung inflation. A complete interpretation would require the estimates and uncertainty, along with clear information on repeated measurements and participant-level correlation.

The study also illustrates why an explicit outcome definition is not enough to evaluate reproducibility. A mean and standard deviation can describe central tendency and spread, but a reproducibility assessment may require details about repeat scans, agreement, or variance components. The registry does not report those analysis details or the observed values. This distinction matters because a study objective, a measurement protocol, and evidence from the resulting data are separate elements.

Finally, the record shows why design labels and the primary comparison need to be read together. Although prone and supine scan groups are described, the primary endpoint is framed around supine measurements at different inflation levels, within a single-group, nonrandomized study. Recognizing that structure prevents an unsupported interpretation of the arms as a conventional control comparison. The statistical importance of the study lies in its measurement question, while the lack of reported numerical findings limits what can be concluded from the registry record.

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 main limitation for interpreting this study from the registry record is the absence of numerical primary outcome results. ADC means and standard deviations for the stated inflation levels are not reported, nor are contrasts, confidence intervals, or test results. The primary measurement question can be described, but the observed variability and its precision cannot be evaluated.

The outcome description says only supine MRI scans were performed for the primary ADC comparison, while the arm descriptions include both prone and supine scans. The registry does not explain how these descriptions fit together. This makes the relationship between the named groups and the primary analysis unclear, and prevents the arm labels from serving as a basis for a posture comparison.

The record does not describe whether measurements at the different vital-capacity levels were paired within participants, whether repeated scans were taken, or how the correlation among measurements was handled. It also does not report the analysis population, endpoint-specific participant counts, or missing-data methods. The enrollment entry alone cannot resolve those questions.

Additional limitations include the absence of a reported statistical analysis plan, sample-size justification, interim-analysis information, and multiplicity strategy. The adverse-event entry lists zero participants at risk for the prone group, but the registry does not explain that entry or give adverse-event ascertainment details. These limitations concern what is reported; they do not establish that a particular procedure or analysis was absent from the study itself.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Repeatability in Hyperpolarized 3-Helium With MRI — NCT03776747.
• Registry record last updated 2023-11-01; status last verified 2023-10.
• Results first posted 2023-11-01.
• 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

NCT03776747, titled “Repeatability in Hyperpolarized 3-Helium With MRI,” is recorded as a completed Phase 4 study with nonrandomized allocation, no masking, and a single-group model. Enrollment is listed as 18. The study began on 2008-07-22, with primary completion recorded as 2012-06, and the sponsor is Eric A. Hoffman.

The study concerns hyperpolarized 3-Helium MRI in healthy adult subjects. Its primary endpoint is mean ADC in ADC (cm2/sec), with standard deviation named as the dispersion measure. The primary outcome description compares supine MRI ADC values at 20%, 60% and 100% vital capacity.

The registry record does not report numerical primary outcome results, analysis details, or the endpoint-specific analysis population. It records zero serious adverse events, zero other adverse events, and zero deaths for the supine group among 18 at risk; the prone group is recorded with zero at risk and zero event counts.