Examining Cognitive Function and Brain Abnormalities in Adults With Sickle Cell Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Examining Cognitive Function and Brain Abnormalities in Adults With Sickle Cell Disease (NCT00528801), a registered phase not stated study. The primary outcome is Wechsler Adult Intelligence Scale (WAIS)-III Performance IQ.

2. Clinical Question

The clinical question was whether neurologically intact adults with sickle cell disease differed from adults without sickle cell disease in cognitive functioning and brain-imaging findings. The primary cognitive measure was WAIS-III Performance IQ. The study also assessed brain lacunae and total cortical gray matter volume using MRI measures.

This is an observational comparison, not a randomized trial of treatment. Its question concerns differences between groups at the time of assessment, rather than whether a treatment changes cognitive function. The registry describes the assessments as occurring within 2 months of signing informed consent. It does not report whether brain-imaging findings were related to IQ in a separate analysis.

3. Trial Design

The registry describes a completed cross-sectional study involving adults with and without sickle cell disease. Participants completed screening questionnaires, a neuropsychological testing battery, and MRI testing. Enrollment was 212. The registry reports that enrollment ended in May 2008 and lists the study status as completed.

Cases were patients diagnosed with sickle cell disease, confirmed by hemoglobin electrophoresis. Controls were persons without sickle cell disease, also confirmed by hemoglobin electrophoresis. The record says controls were matched to cases by age, gender, and education level. It does not report the matching procedure, whether matching was individual or group-based, or how the analysis accounted for matching.

This was not a randomized comparison. The registry does not state an allocation method, and the groups represent disease status rather than assigned study treatments. Consequently, the design can describe measured differences between the groups but cannot by itself establish that sickle cell disease caused any observed difference. Other group differences, including factors not captured by matching, could be relevant.

The primary outcome was mean WAIS-III Performance IQ, measured within 2 months of signing informed consent. The registry also lists two secondary outcomes: participants with brain lacunae measured by clinical MRI and total cortical gray matter volume measured by volumetric MRI. The registry record does not report the planned analysis methods for these outcomes, the timing of MRI relative to testing beyond the general assessment timeframe, or whether any additional eligibility criteria applied.

Although the registry records 212 participants, it does not report how many participants were included in each arm or in each outcome analysis. The results needed to assess the magnitude and precision of group differences are 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: The NP Battery and the MRI could be scheduled in either order. A 4 week visit window was set between screening and the first of the two procedures. An additional 4 week window was set between the first procedure and the second.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per protocol, no imputation used.

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 Wechsler Adult Intelligence Scale (WAIS)-III Performance IQ, measured over Within 2 months of signing informed consent..

The primary endpoint was mean Wechsler Adult Intelligence Scale, Third Edition (WAIS-III) Performance IQ, expressed in points on a scale. The registry describes this measure as an assessment of neurocognitive dysfunction in neurologically asymptomatic adults with sickle cell disease. It also identifies it as the primary outcome for the study.

Performance IQ combines scores from seven subtests: picture completion, picture arrangement, block design, object assembly, digit symbol, matrix reasoning, and symbol search. The registry describes the IQ scale as having an average of 100 and a standard deviation of 15. It cautions that the Wechsler intelligence scales are not considered adequate measures of extremely high and low intelligence, with scores above 160 and below 40, respectively.

For a group comparison, a mean gives a measure of the group’s average score, while the standard deviation describes the spread of individual scores around that mean. Those summaries can help characterize typical performance and variability, but neither reveals the full distribution of scores. The registry specifies the mean and standard deviation as the outcome summary measures; it does not report the actual group summaries or a comparison estimate.

The endpoint is relevant to the study’s stated question because it operationalizes cognitive performance using a standardized assessment. It does not measure every aspect of cognition, and a group average cannot describe every participant’s abilities. The registry record does not report the observed WAIS-III Performance IQ results, so the magnitude and precision of any difference cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s primary outcome is a continuous measure: WAIS-III Performance IQ in points. In general, a continuous outcome can take many values along a scale, and group comparisons often summarize each group with a mean and a measure of spread. The registry specifies the mean and standard deviation. A mean describes the average score, while a standard deviation describes variability among observations. The registry does not report the actual summaries or the method used to compare them.

What does a mean comparison estimate?

In general, a difference between group means expresses the separation of the average scores on the outcome scale. Its interpretation depends on the scale, the population, the data included, and the analysis method. An estimate should be considered alongside its uncertainty, commonly expressed with a confidence interval. The registry does not report an estimate or confidence interval for WAIS-III Performance IQ, so neither its direction nor its precision can be evaluated from the registry record.

What can a confidence interval tell a reader?

In general, a confidence interval represents uncertainty around an estimated quantity under the assumptions of the analysis. A wide interval indicates that a range of effects remains compatible with the data; a narrow interval indicates greater precision. Precision is not the same as clinical importance, and an interval’s interpretation also depends on the quality of the measurement and study design. No confidence interval for the primary outcome is reported in the registry record.

How should matching be interpreted?

The registry says controls were matched to cases by age, gender, and education level. In general, matching is a design approach intended to make comparison groups more similar on selected characteristics. Matching does not automatically control every potential source of difference, nor does it guarantee that the analysis properly accounts for the matched design. The registry does not report how controls were matched or how matching entered the statistical analysis. It would therefore be inappropriate to assume a particular paired or adjusted analysis.

What does the cross-sectional design permit?

In general, a cross-sectional study measures characteristics during a defined assessment period and compares groups at that point. It can describe associations and group differences, but it generally cannot establish temporal ordering from those measurements alone. This study assessed cognitive and MRI measures in adults with and without sickle cell disease; the registry does not describe repeated follow-up measurements for the primary outcome. The design should not be interpreted as a randomized treatment comparison.

How should the MRI measures be understood?

The registry lists participants with brain lacunae measured by clinical MRI and total cortical gray matter volume measured by volumetric MRI as secondary outcomes. In general, a binary outcome such as whether a feature is present is summarized differently from a continuous volume measure. A volume measure may be summarized with a mean and spread or analyzed using another method, depending on its distribution and the study plan. The registry does not report the analysis method, group results, or uncertainty for either MRI outcome.

What is the role of statistical significance?

In general, a p-value is a measure of compatibility between observed data and a specified null model; it does not quantify the probability that a hypothesis is true or the size of an effect. A small p-value does not by itself show that a difference is important, while a larger one does not prove that groups are equivalent. Effect estimates and their uncertainty are needed for a fuller interpretation. The registry does not report p-values or an inferential analysis for the primary outcome.

The registry notes that three outcome measures and two analyses are recorded, but it does not describe the statistical plan, the relationship between analyses and outcomes, or any adjustment for multiple comparisons. No particular model, test, covariate adjustment, or distributional assumption can be attributed to the study from the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Phase I: Cases", "Phase I: Controls")
n   <- c(144, 45)
m   <- c(90.6, 95.9)
sp  <- c(12.7, 12.13)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Phase I: Cases  144  90.600  12.700  88.508  92.692
CARM  Phase I: Controls  45  95.900  12.130  92.256  99.544

11. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures and two analyses. The primary outcome is mean WAIS-III Performance IQ; the secondary outcomes concern brain lacunae and total cortical gray matter volume. The record does not explain how the two analyses relate to the outcome measures, identify a hierarchy among secondary outcomes, or state whether any multiplicity adjustment was planned or used. A statistical plan is not reported in the registry record.

In general, testing several outcomes or conducting several analyses creates more opportunities for apparently notable results to arise by chance. An analysis plan can address this by identifying a primary comparison in advance, specifying which analyses are confirmatory or exploratory, and describing any adjustment for multiple testing. Without those details, the interpretation of any reported p-values would need care. Here, the registry does not report the outcome results or p-values, so the consequences of multiplicity cannot be assessed.

The primary outcome population is described as per protocol, with no imputation used. In general, an analysis without imputation does not fill missing outcome values with modeled or substituted values. This does not establish how many data points were missing, why they were missing, or whether complete observations differed from those without observed outcomes. The registry record does not report outcome-specific missingness, exclusions, or analysis counts.

The enrollment figure does not establish the number analyzed for any particular outcome. Group sizes, participant flow, and the handling of incomplete assessments are not reported in the registry record. The record also does not describe a prespecified sample-size justification or interim analyses. These omissions limit assessment of the planned analysis and the precision that the study could achieve.

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

The registry record identifies a completed cross-sectional investigation of cognitive and MRI measures in adults with and without sickle cell disease. It specifies WAIS-III Performance IQ as the primary outcome and describes the assessment procedures and comparison groups. It does not report the numerical primary or secondary outcome findings. Accordingly, the record does not establish the direction or size of any group difference, nor how precisely such a difference was estimated.

Even when an observational study reports a difference between groups, that finding is not equivalent to evidence that group membership caused the difference. Participants were not assigned at random to have or not have sickle cell disease. The registry describes matching on age, gender, and education level, but does not report how matching was implemented or which other factors were considered. Unmeasured or unreported differences may remain relevant to interpretation.

WAIS-III Performance IQ is a standardized measure based on several subtests, not a complete account of cognitive function. The registry describes limitations at extremely high and low intelligence levels. A group mean would also not convey the range of individual scores or show whether every participant’s experience resembled the average. The actual score distributions are not reported in the registry record.

The MRI outcomes are also specific measures rather than comprehensive descriptions of brain structure or function. The registry names brain lacunae and cortical gray matter volume, but gives no outcome values or analysis details. The record therefore does not support conclusions about the prevalence or magnitude of these findings in either group, or about their relationship to cognitive scores.

The study’s findings should not be treated as evidence for or against a treatment. The record describes assessment and comparison, not a therapeutic intervention. It also does not report changes over time, so the results cannot be used to characterize cognitive trajectories from this registry information alone.

13. Why This Trial Matters Statistically

This study is statistically notable as an observational comparison that brings together a standardized cognitive measure and MRI assessments in adults with and without sickle cell disease. The registry identifies a specific primary outcome, mean WAIS-III Performance IQ, and describes the assessment components that contribute to it. It also distinguishes this cognitive endpoint from MRI-based secondary outcomes.

For readers evaluating a clinical study, the distinction between a defined outcome and a reported result is important. A registry entry can establish what investigators intended to measure and describe the broad design, but interpretation of findings requires group summaries, effect estimates, uncertainty, and analysis details. Those numerical results are not reported in the registry record. The record therefore describes the study question more fully than it documents the evidence needed to assess the answer.

The comparison also illustrates why observational design matters. Cases and controls were described as matched on age, gender, and education level, but the statistical handling of matching is not reported. Matching and analysis are related but distinct parts of a study: the design determines how participants are selected, while the analysis determines how the resulting data are compared. Without the analysis description, the extent to which the comparison accounts for matching cannot be evaluated.

Finally, the combination of cognitive and imaging outcomes raises questions about outcome hierarchy, missing data, and multiplicity. The registry identifies three outcome measures and two analyses, yet does not report a statistical plan or the outcome-specific results. These are not reasons to presume that the study was conducted improperly; they are limits on what can be learned from the registry record. Clear reporting of analysis populations, estimates, uncertainty, and missingness would be necessary to judge the strength and precision of the findings.

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 interpretation is that the registry record does not report the primary or secondary outcome results. There are no group-specific WAIS-III Performance IQ means or standard deviations, no estimated between-group comparison, and no confidence interval or p-value. The MRI outcome findings are also not reported. Thus, the magnitude, direction, and precision of the findings cannot be evaluated.

The record describes 212 enrolled participants but does not report the number in each arm or the number contributing data to each outcome. It states that the analysis population was per protocol and that no imputation was used, but does not define the relevant protocol criteria or report the extent and pattern of missing data. Participant flow, exclusions, and outcome-specific analysis populations are not reported in the registry record.

The control group was described as matched to cases by age, gender, and education level. The registry does not explain the matching method, whether each case had a matched control, or whether the statistical analysis accounted for matching. It also does not report adjustment for other potential differences between groups. Because the study was cross-sectional and not randomized, causal interpretation would be limited even if outcome estimates were available.

The registry does not report a statistical analysis plan, sample-size justification, interim analyses, or methods for handling multiple outcomes. It does not explain how the two analyses relate to the three outcome measures. These omissions constrain assessment of whether the reported analyses, if any, were prespecified and how their results should be interpreted.

The record lists 0 in the at-risk and affected fields for serious and other adverse events, while deaths are recorded as null. Those entries do not describe the completeness or scope of safety surveillance for this non-treatment study, and they should not be treated as a detailed account of adverse events.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Examining Cognitive Function and Brain Abnormalities in Adults With Sickle Cell Disease — NCT00528801.
• Registry record last updated 2017-03-21; status last verified 2017-02.
• Results first posted 2009-11-26.
• 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

NCT00528801 is a completed cross-sectional study titled “Examining Cognitive Function and Brain Abnormalities in Adults With Sickle Cell Disease.” The registry lists UCSF Benioff Children's Hospital Oakland as sponsor and reports enrollment of 212 participants. Cases had sickle cell disease confirmed by hemoglobin electrophoresis; controls did not have the disease and were described as matched by age, gender, and education level.

Participants completed screening questionnaires, a neuropsychological testing battery, and MRI testing. The primary outcome was mean WAIS-III Performance IQ, assessed within 2 months of signing informed consent. Secondary outcomes concerned brain lacunae and total cortical gray matter volume.

The registry describes a per-protocol analysis population with no imputation. It does not report group outcome results, estimates of between-group differences, uncertainty, or the detailed statistical plan. Consequently, the record establishes the study’s question and broad design but does not permit evaluation of the observed cognitive or imaging findings.