Alpha-1 Carrier Genomics Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Alpha-1 Carrier Genomics Study (NCT02810327), a registered phase not stated study. The primary outcome is Number of Participants With Abnormal Sequences in SERPINA1 Genes.

2. Clinical Question

The scientific motivation was to explore why some people with the MZ genotype develop COPD while others do not. The investigators planned to examine whether additional changes in the Alpha-1 gene correlate with COPD history. This is a question about genetic findings and their relationship to disease history, not a randomized test of a treatment.

The registry describes questionnaires about lung health and history and an at-home finger stick to collect blood spots for genetic testing. The study summary says participants would receive their results and have access to genetic counseling at the conclusion of the study. It does not state that the genetic findings were intended to establish a cause of COPD in an individual participant.

3. Trial Design

The registry record identifies the study as the Alpha-1 Carrier Genomics Study, sponsored by the Medical University of South Carolina. It lists an enrollment of 117 and a status of completed. The study start is recorded as 2015-02, and primary completion as 2017-04.

Participants had previously tested as MZ (PiMZ) for Alpha-1 antitrypsin deficiency. The record separates them into a group with symptoms or a clinical diagnosis of COPD and a group without symptoms or a clinical diagnosis. The comparison therefore uses symptom or diagnosis status to define the groups; it is not a randomized treatment allocation. The allocation method is not stated, and the registry cautions that the groups are not a like-for-like control comparison.

The listed intervention is genetic sequencing. The study summary describes questionnaires and an at-home finger stick, with blood spots used for genetic testing and comparison with COPD history. The primary outcome is a count of participants with abnormal sequences in SERPINA1 genes, assessed at the end-of-study next-generation sequencing result.

The record does not report a detailed recruitment strategy, eligibility criteria beyond the MZ genotype and group descriptions, blinding procedures, or a fuller protocol for sequencing and outcome assessment. It also does not report the rationale for the planned enrollment or whether enrollment changed during the study. Those details should not be inferred from the completed status or the listed enrollment.

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

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: Individuals age 18 and over with previous MZ results for Alpha-1 antitrypsin deficiency and AAT level in the lower MZ quartile (\<16uM).

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Abnormal Sequences in SERPINA1 Genes, measured over End of study NGS Result.

The primary endpoint is the number of participants with an additional SERPINA1 variant of known or possible significance detected by next-generation sequencing. The registry expresses this as a participant count and sets the timeframe at the end-of-study sequencing result. In practical terms, it records whether a participant had such a finding, rather than measuring a continuous quantity such as lung function.

This endpoint is relevant to the study’s stated aim because the investigators wanted to examine portions of the Alpha-1 gene that are not routinely tested and assess whether other gene changes correlate with COPD history. Counting participants with an additional variant provides a way to describe the frequency of those findings in each symptom-defined group. The outcome alone, however, does not establish that a variant caused COPD or that it predicts an individual’s future health.

The registry record does not give the number of participants meeting the endpoint in either group, a group-specific percentage, or an estimated difference between groups. It also does not specify how variants were classified beyond “known or possible significance,” or report the detailed criteria used for that classification. Without those results and methods, the endpoint can be described, but its observed pattern and precision cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

A binary outcome indicates whether each participant did or did not meet a defined condition. For this study, the primary outcome is the presence of an additional SERPINA1 variant of known or possible significance. A participant count can be reported for each symptom-defined group. If group sizes and counts are available, a comparison may also express the frequency of the finding in each group and quantify the difference or association. The registry record does not report the endpoint counts or the method used for the primary comparison, so no numerical effect estimate can be interpreted.

In general, a confidence interval describes a range of values compatible with the observed data under a specified statistical method. It conveys uncertainty around an estimate; it is not a guarantee that the true value lies in the interval. A narrow interval generally indicates more precise estimation than a wide interval, assuming the method and model are appropriate. No confidence interval for the primary outcome is reported in the registry record, so the precision of a group comparison cannot be judged from it.

In general, a p-value measures how unusual data at least as inconsistent with a null hypothesis would be under the assumptions of a chosen statistical model. It does not measure the probability that the null hypothesis is true, the size or importance of an association, or whether the result is free of bias. The registry record does not state a p-value or the inferential test used for the primary endpoint. The sample-size assumptions refer to a two-sided significance level of 0.05, but this planning assumption does not establish which method was used for the analysis.

The record describes a comparison between people with and without COPD symptoms or diagnosis, rather than a randomized comparison. General statistical interpretation of such groups requires attention to how participants entered each group and to characteristics that may differ between them. Adjustment can sometimes address measured differences, but it cannot automatically eliminate bias from unmeasured factors or inaccurate measurement. Whether adjustment was used, and which variables might have been considered, is not reported in the registry record.

Sample-size calculations are planning tools. The assumptions recorded for the planning illustration are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the target effect is described as a stated fraction of the observed effect. Such calculations do not represent observed power after the study, and they do not show that the study was adequately powered for every possible effect. The registry record does not report the original study’s sample-size justification. Any planning illustration based on an observed effect should be treated as a hypothetical design calculation, not as evidence that the result was likely to be detected or that a non-significant finding would establish no association.

For count data, the number of participants meeting an endpoint matters alongside the group size. When events are sparse, estimates can be unstable and conventional approximations may perform poorly. General methods for sparse binary data can differ in how they estimate uncertainty, especially when one group has no events. The primary endpoint counts are not reported in the registry record, so it is not possible to determine whether sparse-data methods were relevant or how they were handled.

Over-dispersion is a general issue for count outcomes when observed variability exceeds what a chosen model assumes. It can make standard errors too small if ignored. This study’s primary endpoint is recorded as a participant count for a binary outcome, rather than a repeated event count, and the registry does not report a model or dispersion estimate. Over-dispersion should therefore not be presumed to have occurred or to have been tested.

The registry record lists one primary outcome and one analysis. It does not report the analysis model, the handling of multiple comparisons, or whether secondary or exploratory analyses were conducted. Nor does it describe a prespecified statistical analysis plan. These are important distinctions: a stated endpoint identifies the question, while the analysis plan specifies how data are converted into estimates and uncertainty. Without the latter details and the primary results, the statistical evidence cannot be independently appraised from the registry record.

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("MZ Heterozygote With Symptoms of COPD", "MZ Heterozygote Without Symptoms of COPD")
n      <- c(69, 34)
events <- c(6, 0)
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  MZ Heterozygote With Symptoms of COPD  69  6  8.7  3.3  18.0  4.0  17.7  4.1  17.7
ARM  MZ Heterozygote Without Symptoms of COPD  34  0  0.0  0.0  10.3  0.0  10.2  0.1  10.0

11. Multiplicity, Missing Data and Analysis Populations

The record identifies one primary outcome and one analysis. It does not report whether other outcomes or subgroup analyses were planned, whether additional genetic comparisons were conducted, or how any multiplicity was handled. When many hypotheses are tested, the chance of at least one apparently notable finding can rise; general approaches to multiplicity include adjusting thresholds or clearly distinguishing confirmatory from exploratory analyses. The registry record does not state whether such an approach was used, so no correction should be assumed.

Missing-data methods are not reported in the registry record. It does not state whether all enrolled participants completed sequencing, whether any samples failed quality checks, how unavailable questionnaires or COPD histories were treated, or whether participants with missing information were excluded from the primary analysis. The endpoint denominator and the number of missing endpoint assessments are not reported.

The analysis population is also not described. The registry record does not say whether the analysis included every enrolled participant, only participants with usable sequencing results, or another defined group. For a genetic endpoint, sample availability and the rules for interpreting sequence results can affect which participants contribute to the analysis. Without these details, it is not possible to assess whether exclusions or missing results could have altered the comparison.

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.

The serious adverse event figures are listed separately for the two symptom-defined groups. The registry reports 0 participants affected among 76 at risk in the group with COPD symptoms and 0 affected among 41 at risk in the group without COPD symptoms. Deaths are recorded as 0 in each group. These are the posted serious adverse event counts; they are not results for the primary genetic endpoint.

A zero count in the registry means that no affected participants are recorded for the relevant category in that group. It does not prove that no events occurred outside the reporting period or that every possible safety outcome was captured. The record does not describe the adverse-event collection window, ascertainment procedures, or whether non-serious adverse events were collected. It also does not list serious adverse event terms.

The figures should be read as descriptive safety reporting, not as a randomized comparison of safety between treatments. The groups are not treatment arms in a like-for-like control comparison, and the study intervention is genetic sequencing. The registry record does not provide a causal safety analysis.

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

The study addresses a specific question: whether additional SERPINA1 sequence findings of known or possible significance are present among MZ participants with COPD symptoms or diagnosis, and how that compares with MZ participants without those features. The registry record makes the endpoint and the two group definitions clear. It also describes the intended use of questionnaires and blood spots for genetic testing.

What the record does not establish is the answer to that question. Numerical results for the primary endpoint are not reported in the registry record, so no direction or magnitude of a group difference can be stated. There is also no reported confidence interval or p-value for the primary outcome. The posted record therefore does not support a conclusion about how often additional variants were found or whether their frequency differed between groups.

Even if group-specific results were available, a difference would be an association in these groups, not proof that a variant caused COPD. The comparison is not randomized, and allocation is not stated. People in the groups may differ in other ways, and the record does not explain whether the analysis accounted for such differences.

The outcome is also limited to additional variants meeting the registry’s description of known or possible significance. It does not, by itself, establish the clinical meaning of every detected sequence change. The record does not report variant-classification criteria, validation procedures, or results by variant type.

The completed status and enrollment describe study conduct, not the strength of evidence for the primary question. The serious adverse event counts are separate safety information and cannot fill the gap in the primary genetic results. The most defensible reading is that this study was designed to investigate a genetic correlate of COPD history in MZ participants, while the numerical findings and the methods needed to evaluate them are not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically interesting because it links a genetic question to a comparison defined by existing clinical status. The investigators sought to look beyond routinely tested portions of the Alpha-1 gene and examine whether additional SERPINA1 findings correlate with COPD history. That framing makes the distinction between association and causation especially important: the study compares groups that already differ in symptoms or diagnosis rather than assigning participants to an exposure at random.

The endpoint is a participant count, which is easy to describe conceptually but depends on clear definitions and complete ascertainment. The meaning of “known or possible significance,” the sequencing procedures, and the rules for determining which results qualify all affect the outcome. The registry record provides a concise endpoint description but does not report those operational details or the numerical findings.

Statistical interpretation also depends on the denominator and the precision of the comparison, not just on whether variants were detected. Without group-specific endpoint counts and an uncertainty estimate, readers cannot judge how stable a difference might be or whether the available data are compatible with a range of effects. A planning calculation is not a substitute for those observed results.

The record’s explicit warning that the groups are not a like-for-like control comparison helps prevent an overly causal interpretation. It also highlights why analysis details matter: differences associated with symptom status could reflect other measured or unmeasured participant characteristics. The registry does not report how such factors were handled.

Ultimately, the statistical value of this record is in defining a focused question and a measurable endpoint, while also exposing important reporting gaps. A complete interpretation requires the primary results, methods for variant classification, and details of the analysis population and statistical approach.

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 are apparent from the registry description. First, the primary outcome is defined as an additional SERPINA1 variant of known or possible significance, but the criteria separating known from possible significance are not reported. The registry also does not describe sequencing quality controls, validation procedures, or how uncertain findings were handled. Those details can affect which participants are counted as meeting the endpoint.

Second, the groups are defined by COPD symptoms or clinical diagnosis, but the record does not specify how symptoms were assessed, how a diagnosis was confirmed, or whether the same criteria were applied in both groups. Questionnaires about lung health and history are described, but their content and measurement properties are not reported. The timing of COPD assessment relative to genetic testing is also not specified beyond the stated endpoint timeframe.

Third, the comparison is not randomized, and allocation is not stated. Group differences may therefore reflect factors other than the genetic findings under study. The registry record does not report whether potential confounders were measured or adjusted for, and it does not describe blinding of laboratory personnel or outcome assessors.

Finally, the registry does not report primary outcome counts, missing-result handling, analysis-population criteria, or the statistical model. It does not give a sample-size justification for the original study. These omissions prevent assessment of the observed association, its precision, and the robustness of the analysis. The conclusions that can be drawn from the registry record are accordingly limited to the study question, design description, and reported safety counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Alpha-1 Carrier Genomics Study — NCT02810327.
• Registry record last updated 2019-07-22; status last verified 2019-05.
• Results first posted 2019-07-22.
• 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 Alpha-1 Carrier Genomics Study (NCT02810327) was sponsored by the Medical University of South Carolina and is listed as completed. Enrollment is recorded as 117, with a study start of 2015-02 and primary completion of 2017-04. The study concerned MZ (PiMZ) participants with and without COPD symptoms or a clinical diagnosis.

The primary endpoint was the number of participants with an additional SERPINA1 variant of known or possible significance detected by next-generation sequencing, assessed at the end-of-study sequencing result. The registry record does not report the numerical primary outcome results, the detailed analysis method, missing-data handling, or the original sample-size justification.

Serious adverse event reporting lists 0 affected participants among 76 in the group with COPD symptoms and 0 among 41 in the group without symptoms; deaths are recorded as 0 in each group. These safety counts do not answer the primary genetic question.