Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI (NCT01569568), a registered phase not stated study. The primary outcome is Concentration of Glutamine and Myoinositol.

2. Clinical Question

3. Trial Design

This is a comparison of participants with OTCD and healthy controls using imaging and cognitive assessments. The record lists MRI scanning and cognitive testing as the study procedures. MRI assessments included 1H MRS, DTI, and fMRI; the arm descriptions also specify neuropsychological testing. The registry record does not describe a treatment assignment or randomization process. It explicitly indicates that this is not a randomized comparison and that allocation is not stated.

The registry lists enrollment as 49. The arm descriptions specify males and females ages 7-60 years who could undergo MRI and cognitive testing. The primary outcome population description states that two OTCD patients and one healthy control were excluded due to excessive head motion. This exclusion is relevant because head motion can affect the availability or quality of imaging measurements. The record does not give further details about participant flow or whether those exclusions applied to every outcome.

The study began in 2010-09, had primary completion in 2014-08, and is marked COMPLETED. The sponsor is Andrea Gropman. These administrative details establish the study’s recorded timeline and status, but do not supply information about the statistical plan or the results of the primary comparison. A sample-size justification, interim analyses, and a fuller account of the study design are not reported in the registry record.

Because the groups were not randomized, any group contrast is descriptive and may reflect differences between participants beyond OTCD status. Healthy controls provide a reference group for the planned assessments, but the registry record does not establish that the groups were otherwise comparable.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Two OTCD patients and one healthy control were excluded due to excessive head motion.

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 Concentration of Glutamine and Myoinositol, measured over Baseline.

The listed primary endpoint is the concentration of glutamine and myoinositol at baseline, measured in mM. The record describes quantification from 1H magnetic resonance spectroscopy (MRS) using LCModel. It explains that a metabolite’s tissue concentration is related to the integrated amplitude, or area under the curve, of the MRS signal. Measurements were obtained from two brain areas: posterior cingulate gray matter (PCGM) and parietal white matter (PWM).

The study’s stated purpose is to evaluate brain and cognitive changes in people with OTCD relative to healthy individuals. Brain-metabolite concentrations are therefore relevant as imaging measures for the study’s comparison. The protocol description says the instrument summates data at each time point to generate one value for the area under the curve; it does not provide measurements at each time point. The endpoint is listed as a mean with standard deviation as its dispersion measure.

The registry record does not report the endpoint’s group means, standard deviations, difference between groups, or a confidence interval. Thus, the endpoint definition explains what was intended to be measured, but does not reveal the observed concentration values or the precision of a comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean and standard deviation describe?

The primary outcome is specified as a mean of a continuous measure, with standard deviation as the measure of dispersion. In general, the mean is the arithmetic average of measurements in a group. The standard deviation describes how spread out the individual measurements are around that average. It is not the same as the uncertainty in the mean: uncertainty in an estimated mean depends on the amount of information and the variability in the data. The registry record does not report the outcome means or standard deviations, so these features cannot be evaluated for this study.

How is the MRS measure constructed?

The registry description relates metabolite tissue concentration to the integrated amplitude, or area under the curve, of an MRS signal. It says the signal is acquired in the time domain and usually viewed and analyzed in the frequency domain, with the frequency-domain representation derived by Fourier Transform. The protocol selects 257 averages, and the machine summates the data at each time point to generate one value for the area under the curve. The description specifically notes that measurements at each time point are not available. LCModel is identified as the method used for automatic quantitation of spectroscopy data.

The measurement was made in two different brain areas containing different kinds of brain matter: PCGM and PWM. These are distinct measurement locations, not interchangeable readings from a single region. When interpreting any results, the region and metabolite being summarized would therefore matter. The registry record does not provide the numerical concentrations by region or metabolite.

What would a group comparison mean?

In general, a group comparison evaluates whether the observed measurements differ between groups, while accounting for the variability and amount of data. A confidence interval can convey the uncertainty around an estimated contrast; a test statistic or p-value can assess compatibility with a specified statistical model. Those are complementary summaries, and neither alone establishes practical or clinical importance. The registry record does not report a primary-outcome contrast, confidence interval, test statistic, or p-value. No conclusion about the size, direction, or statistical precision of a difference can therefore be drawn from the endpoint description.

What do the planning assumptions describe?

The sample-size planning illustrations are described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Their target effect is expressed as a stated fraction of the observed effect. Such figures are planning illustrations conditional on those assumptions; they are not the trial’s own design justification and are not observed power. In general, a planning calculation asks how much information might be needed to detect a specified effect under an assumed model. It does not demonstrate that a study did or did not detect an effect. The registry record does not report the trial’s sample-size justification or its own statistical planning process.

The meaning of a normal-approximation illustration depends on whether its assumptions adequately describe the outcome and design. Equal allocation is an assumption for the illustration, not evidence that actual group sizes or allocation followed that pattern. A normal approximation is a modeling choice, not a statement that every measurement has a normal distribution. The record does not provide enough information to assess the fit of such assumptions to the observed imaging data.

What can be said about the analysis plan?

The registry lists 4 outcome measures and 28 analyses. It does not report how these analyses were organized, which tests or models were used for the primary comparison, or whether results were adjusted for multiple comparisons. It also does not report a statistical analysis plan, covariate adjustment strategy, or interim analyses. General statistical methods cannot fill in those missing study-specific details. The group comparison should therefore be read with the available design and outcome information in mind, rather than assuming an unreported model or testing procedure.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures and 28 analyses, but the registry record does not report how multiplicity was handled. When several outcomes, brain regions, or analyses are examined, the chance of finding at least one apparently notable result can increase. In general, multiplicity procedures may control a chosen error rate or distinguish primary from exploratory comparisons. The record does not specify whether such procedures were used, which analyses were considered primary beyond the listed endpoint, or how results across regions and metabolites were prioritized.

Missing-data handling is also not reported in the registry record. The primary outcome population description states that two OTCD patients and one healthy control were excluded due to excessive head motion. That is a specific imaging-related exclusion, but it does not tell whether all remaining participants had usable measurements for every outcome or how any other unavailable data were treated. The record does not describe imputation, complete-case analysis, or sensitivity analyses; none should be assumed.

The endpoint population is not fully characterized in the registry record. The adverse-event data list 20 subjects with OTCD and 29 healthy controls at risk, but those safety figures do not establish the analysis population for the primary imaging outcome. Nor does the record explain whether neuropsychological measures used the same participants as the imaging analyses. The distinction matters: an outcome estimate applies to the participants included in that particular analysis, and exclusions or missing measurements can affect how representative it is.

Overall, the available information identifies a head-motion exclusion but does not provide a full account of analysis populations, missingness, or multiplicity. These omissions limit assessment of how robust any reported pattern would be; the primary outcome results themselves are not reported in the registry record.

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 0% reporting threshold.

The registry’s adverse-event figures list 0 serious adverse events and 0 other adverse events for subjects with OTCD, with 20 at risk in that group. For healthy controls, the figures list 0 serious adverse events and 0 other adverse events, with 29 at risk. These counts describe what is recorded for the listed groups; they do not establish that no events occurred outside the registry’s reporting or observation procedures.

The deaths field is null for both groups. A null entry is not a reported count of zero: deaths are not reported in the registry record. The list of top serious event terms is empty, while the group-level serious-event counts are explicitly 0.

These are descriptive safety figures from a study involving MRI and cognitive assessments, not a comparison of treatments. The record does not provide further detail about event definitions, surveillance, timing, or the method used to collect adverse-event information. The figures should therefore be read narrowly as recorded counts, not as a comprehensive demonstration of safety or evidence about the primary brain-metabolite endpoint.

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

The study record describes an investigation of brain and cognitive measures in people with OTCD relative to healthy individuals. It specifies a baseline MRS endpoint for glutamine and myoinositol, measured in PCGM and PWM, and describes how the spectroscopy signal was quantified. These details establish what the study intended to assess and how the primary measure was defined.

They do not show what concentrations were observed. Group means, standard deviations, and a between-group estimate are not reported in the registry record. Accordingly, the posted information does not indicate whether concentrations were higher or lower in either group, how large any difference was, or how precisely a difference was estimated. It also cannot support a conclusion about the cognitive assessments, whose results are not reported in the registry record.

The comparison is not randomized and allocation is not stated. The healthy control group can serve as a descriptive reference, but the record does not establish that the groups were comparable in other respects. A difference, if reported elsewhere, would not automatically show that OTCD caused it. Conversely, the absence of numerical results in this record should not be interpreted as evidence that there was no difference.

The reported head-motion exclusions further qualify the population to which imaging measurements may apply. The record does not explain how other unavailable data were handled or define the analysis population for each outcome. The adverse-event counts are limited to the recorded figures and do not answer the imaging question.

In short, the registry record gives an objective, measurement definition, study groups, and selected design and safety information. It does not provide the primary outcome findings needed to describe an observed association or its statistical precision. No conclusion about clinical benefit or harm follows from the available outcome information.

13. Why This Trial Matters Statistically

This study is statistically notable for the way it connects an imaging measure to a specific measurement process. The primary endpoint is not a repeated series of moment-to-moment brain readings: the registry description explains that the machine summates data to produce an area-under-the-curve value and that measurements at each time point are not available. That distinction shapes what the endpoint can represent and what kinds of analyses it can support.

The record also distinguishes two brain regions containing different kinds of brain matter. Reporting a concentration without identifying its region would lose important context. The description identifies PCGM and PWM, making clear that interpretation should attend to where a measurement was taken as well as which metabolite was assessed.

At the same time, the registry illustrates why a clear endpoint definition is not the same as a report of findings. The endpoint is named and its quantification described, but group means, variability, and a comparison estimate are not reported. Without those results, neither the magnitude nor the precision of an association can be assessed. Statistical interpretation depends on the observed estimates as well as the measurement method.

The nonrandomized comparison is another important feature. Healthy controls provide a reference group, but the record does not state allocation or establish like-for-like comparability. This design supports descriptive comparisons rather than a randomized causal interpretation. The head-motion exclusions also show how imaging quality can affect which observations contribute to an analysis, while the record leaves other missing-data and analysis-population details unspecified.

Finally, the record lists multiple outcome measures and analyses without describing multiplicity handling. That makes transparent reporting of outcome-specific estimates and analysis methods especially important. Together, these features make the study a useful example of how measurement definitions, design, exclusions, and reporting completeness all shape the conclusions that statistics can support.

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 the primary question is that the registry record does not report the outcome results. Although it defines baseline glutamine and myoinositol concentrations and the method used to quantify them, it gives no group means, standard deviations, contrasts, confidence intervals, or p-values. The direction, size, and precision of any difference are therefore unavailable.

The comparison is not randomized, and allocation is not stated. The record does not establish that OTCD participants and healthy controls were comparable on characteristics other than group membership, nor does it describe adjustment for potential differences. A descriptive group contrast, even if available, would not by itself identify a causal effect of OTCD.

Two OTCD patients and one healthy control were excluded due to excessive head motion. The record does not report further details about imaging quality, other missing measurements, or whether exclusions differed across outcomes. It also does not provide a full analysis-population description, so the scope of the endpoint results cannot be evaluated from the registry record.

The registry lists 4 outcome measures and 28 analyses but does not report multiplicity procedures or identify the statistical methods used for each analysis. The statistical analysis plan, sample-size justification, and interim analyses are not reported in the registry record. These omissions prevent assessment of prespecification and the possibility of selective emphasis among analyses.

For safety, the recorded adverse-event counts are available, but deaths are not reported in the registry record and details of event collection are not given. These limitations are specific to the information recorded and do not establish what may be available elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI — NCT01569568.
• Registry record last updated 2024-03-08; status last verified 2024-02.
• Results first posted 2017-04-14.
• 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

NCT01569568 is a completed study titled “Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI.” It compares participants with OTCD and healthy controls using MRI and cognitive assessments. The record lists enrollment as 49, a start date of 2010-09, and primary completion in 2014-08.

The primary outcome is baseline concentration of glutamine and myoinositol, measured by MRS and quantified using LCModel in PCGM and PWM. The record reports exclusions of two OTCD patients and one healthy control due to excessive head motion, but does not report primary outcome results. It lists 0 serious and 0 other adverse events in each group; deaths are not reported in the registry record. Random allocation, the statistical analysis plan, multiplicity handling, and missing-data methods are not reported.