Self Assembling Peptide P11-4 in Patients With Early Occlusal Carious Lesions: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Self Assembling Peptide P11-4 in Patients With Early Occlusal Carious Lesions (NCT02724592), a randomized phase 1, phase 2 study. The primary outcome is Caries Activity and Progression Assessment Using LASER Fluorescence Readings by Diagnodent® Device..

2. Clinical Question

This is a question about the difference between two treatment strategies in a particular setting: early occlusal lesions on erupting permanent molars. It is not a comparison of P11-4 with no treatment, because the control group received fluoride varnish. Nor does the primary measure directly count lesions or describe a clinical event; it records a device reading related to bacterial activity in a lesion.

The registry describes the study as randomized, controlled, single-blinded and mono-centre. The primary outcome was assessed at 6 months. The registry also lists lesion progression, ICDAS classification and caries activity according to Nyvad criteria as secondary outcomes. The clinical question is therefore broader than the primary device reading, but the primary comparison remains the prespecified focus in the posted outcome record.

3. Trial Design

The registry record describes a randomized, controlled, single-blinded, parallel-group study at a single centre. Its listed phases are Phase 1 and Phase 2, and its status is completed. Enrollment is recorded as 70. The study began in 2013-02, with primary completion in 2014-04. University Medicine Greifswald is listed as the sponsor.

Participants had active early occlusal lesions, ICDAS-II classifications 1–3, on first or second permanent molars at eruption. The intervention group received self-assembling peptide P11-4 (Curodont™ Repair) together with fluoride varnish (Duraphat®). The control group received fluoride varnish alone. Random allocation supports a comparison between these assigned strategies, although the registry record does not report the allocation procedure or concealment method.

Single-blinding is reported, but the registry record does not identify who was blinded or describe how blinding was maintained. The parallel design means the groups were compared over the same follow-up period rather than participants crossing from one treatment to another. The primary outcome was measured at 6 months. Secondary outcomes were also listed at 6 months.

The posted primary outcome data include 31 participants in the intervention arm and 34 in the control arm. Those outcome-specific counts do not by themselves explain how participants moved from enrollment to analysis, and the registry record does not report a participant-flow account or analysis population definition. It also does not report the trial's original sample-size assumptions, a detailed statistical analysis plan, or the methods used to handle missing outcome 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.

Before assignment: No patient declined to participate

Overall Study

Reasons for not completing this period:

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 Caries Activity and Progression Assessment Using LASER Fluorescence Readings by Diagnodent® Device., measured over 6 months.

The primary endpoint is change in caries activity and progression measured by Diagnodent® laser fluorescence. The device measures fluorescence associated with bacterial secretions in a carious lesion. The registry describes readings from 0 to 99, where 0 means no bacterial activity in the lesion and 99 refers to high bacterial and caries activity.

The recorded change is baseline reading minus the reading at the 6-month recall. Under that definition, a higher positive change represents regression, while a smaller positive change or a negative change represents progression. The direction of the subtraction matters: the result is not the 6-month value minus baseline. A comparison of mean changes therefore addresses how much the device readings shifted over follow-up, on average, in one group relative to the other.

A device-based continuous measure can capture degrees of change rather than reducing the result to a simple yes-or-no classification. That makes it useful for comparing average changes between groups. It remains a measure of fluorescence associated with bacterial activity, however, rather than a direct measure of every aspect of lesion status or a patient-centered outcome. The registry record does not report a threshold for a clinically important change, nor does it explain how measurement variability or repeatability was assessed.

7. Results Posted in the Registry

• Intervention: mean 18.60 versus 1.10 on control; difference 17.50 (95% CI 6.37 to 28.63), standardized effect d = 0.76; z-test p = 0.002.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Visual Analog Scale of Lesion Progression (VAS)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Intervention: mean 88.00 versus 49.10 on control; difference 38.90 (95% CI 18.33 to 59.47), standardized effect d = 0.92; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Intervention than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

ICDAS Classification Index

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Intervention: 29.0% (9/31) versus 5.9% (2/34) on control; risk difference 23.1 percentage points (95% CI 5.3 to 41.0), risk ratio 4.94 (1.15–21.10); unadjusted two-proportion z-test p = 0.013.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Intervention than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Caries Activity Assessment According to Nyvad Criteria

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Intervention: 19.4% (6/31) versus 61.8% (21/34) on control; risk difference -42.4 percentage points (95% CI -63.9 to -21.0), risk ratio 0.31 (0.15–0.67); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Intervention than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes use complementary measures: a Visual Analog Scale for lesion progression, the ICDAS classification index, and caries activity according to Nyvad criteria. The posted summaries show differences between the intervention and control groups on these measures, with directions that broadly fit the primary outcome's pattern of greater regression in the intervention group. They do not all represent the same construct or use the same scale, so they should not be combined into a single numerical conclusion.

These measures can offer context for a device-based primary endpoint. Agreement across measures that describe lesion progression or activity may make the overall pattern more coherent, while disagreement could point to differences in what the measures capture. In this record, secondary results are supportive evidence about the observed pattern, not a replacement for the primary comparison. They do not show whether the primary difference translates into an outcome that matters to patients, and the registry record does not report a threshold for clinical importance.

The registry reports unadjusted secondary comparisons and lists no reported secondary analyses. When several outcomes are examined, chance alone can produce apparently notable results. Without a reported multiplicity strategy, secondary p-values and confidence intervals do not have the same confirmatory footing as a single prespecified primary comparison. The registry record also does not explain whether these outcomes were designated in advance as key secondary outcomes or how their analysis was planned.

Accordingly, the secondary endpoint pattern can be read as descriptive corroboration, with appropriate caution. It does not independently establish the magnitude or durability of the primary result. The lack of analysis details and multiplicity adjustment limits how strongly the secondary findings can be used to reinforce a treatment-effect claim.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Visual Analog Scale of Lesion Progression (VAS)
• ICDAS Classification Index
• Caries Activity Assessment According to Nyvad Criteria

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each participant has a change score measured in units on a scale, and the registry reports a mean and standard deviation for each arm. A mean summarizes the group average. A standard deviation describes how spread out individual observations are around that average; it is not the uncertainty in the estimated mean and is not a confidence interval.

The posted group comparison is a mean difference. It is calculated in the direction intervention minus control, consistent with the group means of 18.6 and 1.1 and the reported difference of 17.5. Because a positive change is defined as regression, a positive difference means that the average change was larger in the intervention group. This direction depends on the endpoint's stated subtraction and interpretation; reversing the subtraction would reverse the sign without changing the underlying contrast.

A confidence interval expresses uncertainty around an estimate. In general, a 95% confidence interval is generated by a method that, under its assumptions, would cover the target value in 95% of repeated applications. It is not a probability statement about this particular interval containing the true value. The interval from 6.374 to 28.63 describes uncertainty in the estimated mean difference. Its width reflects both the observed variability and the amount of information contributing to the estimate.

The unadjusted p-value for the primary comparison is 0.002. In general, a p-value measures the compatibility of the data with a specified null model, assuming the model and its conditions. A small p-value is not a measure of effect size, clinical importance, or the probability that the null hypothesis is true. “Unadjusted” means the posted value is not presented as corrected for the number of outcomes or comparisons. The registry record does not report a more detailed model specification or an adjustment for covariates.

Why use a mean difference?

A mean difference retains the original scale of the outcome. It describes the contrast in average change in the scale's units, which can be easier to interpret clinically than a standardized effect. A standardized effect expresses a difference relative to variability and can help compare results measured on different scales, but it no longer has the direct unit interpretation of the mean difference. The posted standardized effect is 0.756; its clinical meaning depends on the scale and context and should not replace the raw-scale estimate.

The outcome is derived from readings whose stated range is 0 to 99. In general, bounded measures can have distributions that differ from a normal distribution, especially near a boundary. The change score also combines two readings from each participant. A standard error or confidence interval for a mean difference relies on assumptions about the sampling distribution and the analysis. The registry record does not describe diagnostic checks, a transformation, or a model that accounts for the baseline and follow-up readings jointly, so the appropriateness of any such choices cannot be assessed from the record.

How do the secondary outcome comparisons differ?

The Visual Analog Scale outcome is also reported as a continuous measure, with group means, standard deviations and a mean difference. ICDAS classification and Nyvad caries activity are reported as counts of participants, so their comparisons are binary-outcome comparisons rather than mean differences. A risk difference expresses the difference between the proportions meeting the recorded outcome in the two arms. The posted risk differences are 0.232 for the ICDAS outcome and -0.424 for the Nyvad outcome, each with its own confidence interval. Their signs must be read using the registry's outcome coding and group order; a risk difference is not a raw difference in participant counts.

For binary outcomes, uncertainty depends on the counts and the denominators. In general, estimates based on relatively few outcome events can be imprecise, and methods for ratios such as risk ratios or odds ratios may behave differently from methods for risk differences. The registry also posts risk-ratio and odds-ratio estimates for these secondary comparisons, but reports no analysis method or adjusted comparison. These measures should not be treated as interchangeable: they answer different questions and can have different numerical scales.

The posted p-values for secondary comparisons are unadjusted. Considering several outcomes increases the chance that at least one comparison appears unusual by chance, even if none reflects a true difference. Multiplicity methods can address that issue, but no such method is reported in the registry record. The secondary results are consequently best read as exploratory or supportive descriptions, rather than as independent confirmatory tests.

Statistical methods are not fully documented in the registry record. It does not report whether the primary analysis was based on intention to treat, a per-protocol population, or another defined set; how missing observations were handled; or whether analyses were adjusted for baseline values. These details matter because they can affect both the estimate and its uncertainty. The posted summary statistics permit description of the reported comparisons, but not reconstruction of every analytic decision.

11. Confidence Intervals and Precision

The primary mean difference is 17.5, with a 95% confidence interval from 6.374 to 28.63. The interval is entirely above zero, which is consistent with a positive average difference under the reported contrast and outcome coding. Its width also shows that the exact size of the average difference is not known precisely: values across a range remain compatible with the data and the method used.

Precision is distinct from the direction of an estimate. The confidence interval indicates uncertainty in the estimated group contrast, not the range of individual participant changes. The standard deviations, 19.8 in the intervention group and 25.8 in the control group, describe variability among observed changes within each group; they are not uncertainty limits around the mean difference.

The interval's interpretation depends on the analysis assumptions, including how observations were selected and how the standard error was estimated. The registry record does not describe missing-data handling, analysis populations, or diagnostic checks. The interval therefore conveys the precision of the posted comparison under its calculation, while leaving some questions about robustness unresolved. It also does not establish whether the estimated difference is clinically important; the registry record does not report a threshold for that judgment.

Secondary confidence intervals vary in width and should be read in relation to their outcome scales. The Visual Analog Scale has a mean-difference interval, while ICDAS and Nyvad are binary outcomes with risk-difference intervals. These intervals quantify uncertainty for different measures, so their widths should not be compared as if they represented the same quantity. Unadjusted intervals also do not account for examining multiple outcomes.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effects, not the trial's original sample-size calculation. For the primary outcome, planning for 100% of the observed effect gives 28 participants per arm for 80% power and 37 participants per arm for 90% power. Planning for 75% of the observed effect gives 49 participants per arm for 80% power and 66 participants per arm for 90% power. Planning for 50% of the observed effect gives 110 participants per arm for 80% power and 147 participants per arm for 90% power.

These figures use a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. The assumed effect is the stated fraction of the observed effect. For these outcomes, the figures are participants per arm, not total participants across the study. The event-total convention applies to time-to-event outcomes, and no such outcome is reported.

In plain terms, 80% power means that, under the planning assumptions and if the assumed effect were the true effect, the design would have an 80% chance of detecting it at the specified significance level. The 90% column represents a higher target chance of detection under the same kind of assumptions. Smaller target effects require more participants because they are harder to distinguish from random variation. This is not observed power; it is a planning illustration using the observed effect as its starting point.

The registry record does not report the original study's sample-size justification or the assumptions used when the trial was designed. The illustration cannot establish whether the completed study was adequately planned for a clinically important effect, particularly because the clinically important threshold is not reported.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 17.500; pooled standard deviation σ = 23.138.
2. n = 2 × (1.96 + 0.842)² × 23.138² / 17.500² = 27.4, rounded up to 28 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 17.5                      # observed difference in means
sigma <- 23.1377242985192                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2724592)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 28 (80% power), 37 (90% power)
 75% of observed effect: n per arm = 49 (80% power), 66 (90% power)
 50% of observed effect: n per arm = 110 (80% power), 147 (90% power)
power.t.test: 28.4 
Simulated power at n = 28 per arm: 0.799 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and three secondary outcomes. The posted comparisons include an unadjusted p-value for the primary outcome and unadjusted p-values for the secondary comparisons. The registry record does not report a multiplicity adjustment, such as a procedure to control the chance of false-positive findings across multiple outcomes. The primary result should therefore be distinguished from the secondary comparisons, which have less confirmatory weight when several tests are considered without adjustment.

The registry record does not report a detailed statistical analysis plan or explain whether outcome definitions, analysis methods and testing order were specified before data were examined. It also does not report interim analyses or stopping rules. These omissions do not establish that such procedures were absent; they mean that they are not reported in the registry record.

Missing-data information is also not reported in the registry record. The posted outcome denominators are 31 for the intervention group and 34 for the control group, but the record does not explain whether these counts reflect all randomized participants, participants with available measurements, or a defined analysis population. It gives no account of missing outcome values, reasons for missingness, imputation, or sensitivity analyses. Thus, the possible influence of missing measurements on the estimates cannot be evaluated from the posted information.

The registry does not state whether the primary analysis followed intention-to-treat principles, used a per-protocol population, or applied another population definition. It does not report adjustment for baseline Diagnodent readings or other covariates. These choices can affect estimates and uncertainty, especially when follow-up outcomes are compared. The posted results can be described as reported, but a full assessment of their robustness requires analysis details that are not reported in the registry record.

15. 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.

For serious adverse events, the registry reports 0 affected participants among 35 at risk in the intervention group and 0 among 35 at risk in the control group. The registry also reports 0 other adverse events in each group and 0 deaths in each group. The serious adverse-event terms list is empty.

These figures describe what was recorded in the registry for the listed at-risk groups. Zero reported events does not prove that an event could never occur or that the two strategies have identical safety profiles. The ability to detect uncommon events depends on the amount of safety observation, and the registry record does not provide a detailed adverse-event collection method, follow-up duration for safety, or a description of events that did not meet the serious-event definition.

The adverse-event denominators are distinct from the outcome-specific counts reported for efficacy. The record does not explain the relationship between these sets of counts or provide participant-level safety information. The safety results should therefore be read as a report of no recorded events in the registry categories, rather than as a comprehensive estimate of risk.

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

The posted primary result is a larger average improvement in Diagnodent change in the group assigned to P11-4 plus fluoride varnish than in the group assigned to fluoride varnish alone. The estimated mean difference was 17.5 units on a scale, with a 95% confidence interval from 6.374 to 28.63. This is an estimate of a group-average contrast over the 6-month follow-up, interpreted using the registry's definition of positive change.

The result does not show that every participant improved, nor does it specify the likely change for an individual. Group means can conceal substantial variation, as reflected in the reported standard deviations. It also does not establish that the measured difference is clinically important: the registry record does not report a minimum important difference or a threshold for meaningful change in Diagnodent readings.

The comparison tests adding P11-4 to fluoride varnish against fluoride varnish alone. It does not answer whether P11-4 alone would have the same result, whether the result would persist beyond 6 months, or whether it applies to different lesion types or clinical settings. The trial is described as mono-centre and concerns early occlusal lesions on erupting permanent molars, so generalization beyond that context requires care.

The unadjusted p-value of 0.002 indicates that the reported mean difference is not easily reconciled with a model of no average difference under the analysis assumptions. It is not proof of causation, a probability that the result is true, or a measure of treatment benefit. The record's missing analysis details and absence of a reported multiplicity plan also limit interpretation. Neither the primary outcome nor the secondary measures alone establish an overall clinical decision.

17. Why This Trial Matters Statistically

This trial is statistically informative because it compares an added treatment component against an active comparator rather than against no care. Interpreting the result therefore requires attention to the actual contrast: P11-4 plus fluoride varnish versus fluoride varnish alone. That distinction prevents attributing the entire observed change to P11-4 without regard to the shared comparator treatment.

The primary endpoint also illustrates why direction and definition matter. The change is baseline minus follow-up, so positive values have the registry-defined meaning of regression. Reading the group difference without attending to that convention could reverse its interpretation. Reporting the raw-scale contrast alongside uncertainty helps readers assess both direction and plausible magnitude.

The secondary measures broaden the picture, but introduce a multiplicity issue. Several endpoints can describe related aspects of lesion status while also increasing the chance of apparently persuasive results by chance. The record's unadjusted comparisons make it important to keep the primary endpoint distinct from secondary evidence.

Finally, the planning illustrations show how required sample sizes depend on the effect targeted: smaller effects require more participants for the same planning power. They are not a substitute for the missing original sample-size rationale. Together, the outcome definitions, confidence interval, active comparator and unreported analysis details show why statistical interpretation depends on more than a p-value alone.

18. 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 registry record gives limited detail on the study's conduct and analysis. Although it identifies the trial as single-blinded, it does not report who was blinded or how blinding was maintained. It describes a randomized design but does not report the sequence-generation or allocation-concealment methods. These details are relevant when assessing the potential for bias.

The primary outcome is a device-derived fluorescence change, not a direct measure of all aspects of caries progression. The record explains the reading scale and the direction of change, but does not report measurement repeatability, validation details, or a clinically important threshold. The posted standard deviations indicate variability in observed change, while the registry record does not explain whether measurement error was considered in the analysis.

The study is mono-centre and focuses on early lesions on erupting first or second permanent molars. That specific population and setting limit how confidently results can be generalized to other lesions, teeth, ages or care contexts. The registry record does not provide demographic characteristics that would help assess representativeness.

Outcome-specific denominators are reported, but participant flow, missing observations and analysis populations are not. The original sample-size rationale, detailed statistical plan, covariate adjustments and missing-data sensitivity analyses are also not reported in the registry record. These gaps prevent a complete assessment of attrition, analytic robustness and the degree to which the completed study was designed to detect a clinically meaningful difference. Follow-up for the primary endpoint is 6 months; longer-term results are not reported in the posted outcomes.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Self Assembling Peptide P11-4 in Patients With Early Occlusal Carious Lesions — NCT02724592.
• Registry record last updated 2021-04-08; status last verified 2021-03.
• Results first posted 2021-04-08.
• 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.

22. Record Summary

NCT02724592 is a completed, randomized, controlled, single-blinded, mono-centre, parallel study sponsored by University Medicine Greifswald. It enrolled patients with active early occlusal carious lesions on erupting permanent molars and compared P11-4 plus fluoride varnish with fluoride varnish alone. The registry lists Phase 1 and Phase 2 and records enrollment as 70.

The primary outcome was change in Diagnodent laser fluorescence readings at 6 months. The posted mean difference was 17.5 units on a scale (95% CI 6.374 to 28.63; unadjusted p = 0.002), with larger positive changes defined as regression. Secondary measures covered lesion progression, ICDAS classification and Nyvad caries activity. No serious adverse events, other adverse events or deaths were reported in the listed groups.

The registry record does not report the original sample-size rationale, a detailed statistical plan, missing-data handling, or multiplicity adjustment. The results should be interpreted as posted group comparisons, with those reporting gaps in mind.