Ahmed Mohammed Morsy＊

Pediatric Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt

Although stringent methodological criteria have been sufficiently fulfilled in both of the study protocol & the commentary article,1,2besides that the study protocol has been designed to permit randomized allocation of participants, which is often considered the gold standard for a clinical trial; however, surgeons increasingly recognized the limitations of a randomized clinical trial, where there are inevitable number of variables that are not amenable for randomization such as, each patient had unique baseline findings,each surgeon had different skills, and each operation involved countless choices about anesthesia, premedication, surgical approach, instrumentation, and postoperative care, all of which challenged the notion that clinical trials are insistently required.3

As a critical appraisal for the clinical trial study protocol of Liu et al.,1potential areas of improvement of the protocol could enhance the study yield, mostly from the statistical analysis point of view still remains. These points summarized here needed to be addressed & considered as follows.

In practice, simple randomization may not ensure balance in some important covariates. Stratification and minimization are not alternatives to covariate adjusted analysis.4The difference between treatment groups in the outcome should be adjusted for baseline score, disease, and demographic covariates, and have to be considered, in particular for known prognostic covariates,such as the duration of symptoms and advanced age that have been negatively correlated with outcomes in previous studies.5,6In addition, a well conducted observational study can be more valuable than randomized controlled trials with distorted randomization, as statistical adjustment for strong predictors of outcome and overall interpretations usually take bias in nonexperimental studies into consideration.7-9

A sub-group analysis10,11to compare the difference between the treatments for the sub-groups of interest should be performed; namely, for moderate and severe cubital tunnel syndrome that have previously shown differences in efficacy of surgical options.12To estimate differences in treatment effect within subgroups (a subgroup effect),13the treatment interaction effect could be examined using multivariate analysis within an appropriate regression model.14

To calculate the study sample size15based on the size of treatment effects, taking into account expected dropout during follow-up to have an appropriate estimate of the sample size needed to detect differential subgroup effects.16Generally,the larger the effect size,17the greater the difference between treatment groups in the outcome measure, and the lower the sample size that is required.

Intention-to-treat analysis18would be the preferred approach for the evaluation of primary outcome measures, particularly to overcome bias that could result when the reasons for non-adherence to the protocol are related to prognosis. This implies that patients are always analyzed in the group to which they were initially randomized19even if they drop out of the study.

Standardized clinical outcome metrics20would be better to be used if possible, as no universally standardized metrics are present to assess clinically relevant improvement in function compared to baseline. Although various rating systems for improvement exist, these have not been universally adopted.21

A reliable and well-validated composite measure could be constructed using “Area under the Receiver Operating Characteristic” (ROC) curve.22Composite measure23in statistics and research design refer to combining multiple individual measures of various outcome parameters24that are assumed to be associated with variation in diagnostic accuracy. ROC curve is an index of overall inherent validity of the test as well as used for comparing the sensitivity and specificity at particular cutoffs of interest.25Composite measures could be developed & validated to assess surgical performance or morbidity in hospitals.26,27

It would be better if an estimate of concordance between two outcome assessors (Inter-rater agreement)28was used to give a report about subjective clinical data dependent on (1) assessor judgment, (2) patient-reported; such as muscle strength, grip and pinch strength of the hand, and sensation.

Author contributions

AMM wrote the paper, read and approved the final version of the paper for publication.

Conflicts of interest

None declared.

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Peer review

Externally peer reviewed.

Open access statement

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License,which allows others to remix, tweak, and build upon the work noncommercially, as long as the author is credited and the new creations are licensed under the identical terms.

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