Mixed Random and Nonrandom Allocation, and Group Randomization Have Been Mislabeled and Misanalysed, Necessitating Reanalysis. Comment on Conner et al. KiwiC for Vitality: Results of a Randomized Placebo-Controlled Trial Testing the Effects of Kiwifruit or Vitamin C Tablets on Vitality in Adults with Low Vitamin C Levels. Nutrients 2020, 12, 2898

We read the report by Conner and colleagues that tested whether kiwifruit or vitamin C affected measures of vitality [1]. The trial is reported as a randomized controlled trial (RCT), but not all participants were allocated randomly, and some participants were group-randomized, which was not accounted for in the analysis. Together, these design choices mean that as published, the statistical analysis and interpretation of results as an RCT are not warranted and corrections are needed.

We contacted the authors to inquire about their design after reading their methods, which included references to ‘batch randomization’ and challenges with stratification. The authors expeditiously shared their data, code, and additional detail on their design. We thank the authors for their collegiality in communication.

Through discussion, we learned that some participants were not randomly assigned, while some were group-randomized, and others individually randomized (see figure at https://doi.org/10.31219/osf.io/ehk3x (accessed on 26 April 2021) for our understanding of the design). We elaborate on the different aspects of nonrandom, random, restricted random, and group random methods at https://doi.org/10.31219/osf.io/ehk3x (accessed on 26 April 2021). The design choices change requirements for the analysis and communication of the trial as an RCT. We outline two errors below.

First, the trial should not be labeled as an RCT because of the methods used. Randomization is generally considered the gold standard to provide unbiased estimates of causal effects [2]. The use of some nonrandom methods, such as assigning kiwifruit to the first groups of participants because of availability, as done by Conner et al., does not permit the causal inferences justified by randomization [3,4], and therefore makes it incorrect and inappropriate for the KiwiC study to be called an RCT.

Second, when participants are randomized in sets of two or more participants (as opposed to each participant being randomized individually), this is conventionally referred to as group-randomized or cluster-randomized and referred to by Conner et al. as ‘batch randomized’. With group-randomization, the model residuals are ‘correlated’ (i.e., the residuals are not independently and identically distributed, iid [5]) and this violation of the assumption of standard analyses must be taken into account during the analysis [6], but they were not. As stated by Murray and colleagues: “Any test that ignores either the extra variation or the limited degrees of freedom will have a type I error rate that is inflated…” [7].

We encourage the authors to provide readers additional detail on their methods as they generously shared with us, which is essential for interpreting this study. We note a similar example of the Primary Prevention of Cardiovascular Disease with a Mediterranean Diet (PREDIMED) trial, in which, just as in this trial, the nonrandom allocation of some of the participants and some group-randomizations were uncovered in a trial audit [8]. In that case, the paper was retracted and republished with a reanalysis to properly consider these factors [8]. The ‘retract and republish’ approach allows for critical issues to be corrected and clarified while simultaneously acknowledging the value of a study through republication. Until corrections are made, causal inferences from this paper are not warranted.

Author Contributions

Conceptualization, C.J.V. with all authors; writing—original draft preparation, C.J.V.; writing—review and editing, all authors. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

In the past 12 months, Dr. Brown has received grants through his institution from Alliance for Potato Research & Education, Egg Nutrition Center, National Cattlemen’s Beef Association, NIH/NHLBI, and NIH/NIDDK. He has been involved in research for which his institution or colleagues have received grants or contracts from Center for Open Science, Gordon and Betty Moore Foundation, Hass Avocado Board, Indiana CTSI, National Cattlemen’s Beef Association, NIH/NHLBI, and NIH/NIA. He has received honoraria from the University of Arkansas. His wife is employed by Reckitt Benckiser. In the last 12 months, Dr. Allison has received personal payments or promises for same from: Alkermes Inc.; American Society for Nutrition; American Statistical Association; Arnold Ventures (formerly the Laura and John Arnold Foundation); Big Sky Health, Inc.; Dynamics AQS; Glanbia; Henry Stewart Talks; Indiana University; Johns Hopkins University; Kaleido Biosciences; Law Offices of Ronald Marron; National Institutes of Health (NIH); Sage Publishing; The Obesity Society; Tomasik, Kotin & Kasserman LLC; University of Alabama at Birmingham; National Academy of Sciences; Medpace/Gelesis; Sports Research Corp.; Whistle Labs, Inc.; Donations to a foundation have been made on his behalf by the Northarvest Bean Growers Association. Dr. Allison is an unpaid member of the International Life Sciences Institute North America Board of Trustees. Dr. Allison’s institution, Indiana University, and the Indiana University Foundation have received funds to support his research or educational activities from: NIH; USDA; Soleno Therapeutics; National Cattlemen’s Beef Association; Eli Lilly and Co.; Reckitt Benckiser Group PLC; Alliance for Potato Research and Education; American Federation for Aging Research; Dairy Management Inc.; Arnold Ventures; the Gordon and Betty Moore Foundation; the Alfred P. Sloan Foundation; and numerous other for-profit and non-profit organizations to support the work of the School of Public Health and the university more broadly. Other authors report no disclosures.

Funding Statement

Supported in part by the Gordon and Betty Moore Foundation and NIH grants R25HL124208 and R25DK090880. The opinions expressed are those of the authors and do not necessarily represent those of the NIH or any other organization.