Review for 10.1186/1471-230X-10-72 (2010)

Reviewer's report
Title:Gastric and intestinal barrier impairment in African adults: a randomised
controlled trial of micronutrient supplementation
Version: 2Date:31 December 2009
Reviewer: Henrik Friis
Reviewer's report:
The manus reports data based on analyses of material from a micronutrient trial
among adults from a community in Lusaka, Zambia. The original
cluster-randomised trial allocated households to supplementation with
micronutrients or placebo for two years, and then crossed-over, and included 500
adults with or without HIV. There was no effect on the primary outcome,
incidence of diarrhea, but a reduction in severe diarrhea and mortality. The
current paper comprises several substudies, somehow nested in this trial, with
potential intermediate outcomes. The strength of the paper is, that it has data
rarely reported from HIV afflicted, low-income populations, and that it aims to
explain the mechanisms behind the effects of micronutrient supplementation.
Major comments:
The description of the substudies and subgroups is not clear. In the Study design
and Methods section, the authors refer to four sub-studies, but they also define
sub-groups by the outcomes as gastric acid or translocation (permeability,
LPS/anti-LPS, sTNFR55) sub-groups (in Table 2).
203 were included in the former and 87 in the latter. It is not clear what the
criteria were for including some of the 500 individuals in the individual
substudies? Furthermore, the timing of the measurements of these outcomes is
also not clear? Fx, gastric pH was measured after 4 to 19 months, while other
outcomes were measured after the cross-over.
Obviously, the study presented is not a straight forward RCT. The title needs to
be changed to reflect this. This is important, because in a RCT confounder are
eliminated or reduced through randomization, and the effects on a well-defined
primary outcome is assessed in a reasonably well-defined study population. In
this case, it is not obvious that the randomization used for the main trial resulted
in baseline equivalence with respect to the substudies? For example, the group
sizes are quite different for the translocation study, and there seem to be
considerable age and sex differences. Lack of statistical difference between the
groups (Table 2) does not rule of confounding. Besides, it is not clear if what is
reported in the table (BMI, MUAC) is measured at baseline. Time of
measurements should also be reported. Furthermore, the two subgroups seem to
be different with respect to BMI? So, it may be more correct to consider this
study to be observational, although nested within a RCT. Consequently, study
limitations need to be discussed.
The multivariate analysis is not adequately described. Which variables were in
the final model – was age and sex controlled for?
Minor comments:
Abstract:
It is not correct that the participants comprised all consenting adults in the
community. In this study, only subgroups of those participated. Baseline
information is lacking, eg HIV prevalence, etc.
Introduction:
The introduction seems to be very long, and contains several categorical
statements, that are not justified. I do not agree that it is controversial that zinc
supplementation reduces risk of diarrhea, and that nutrition is not important to
immunity. Referring to a single reference is not a fair reflection of the evidence.
The effect of a nutritional intervention will depend on the nutritional status of the
population, and a lack of effect can there for be due to the fact that the population
was not deficient. There are a whole range of trials showing that zinc
supplementation does reduce incidence of diarrhea, and a single study not
finding such effect does not change that fact. Similarly, there are plenty of
laboratory animal studies showing that zinc depletion leads disappearance of the
thymus and to impaired cell-mediated immunity.
Methods
Again, selection criteria, and criteria for the timing of the measurements should
be explained
Results
The number of patients recruited in the main trial should not be mentioned here.
The description in of background characteristics could be elaborated on. While it
is correct not to do significance testing based on baseline characteristics in a
proper randomized trial, it may be appropriate here, if it is not based on a random
process. But in the text, irrespective of the p-values, attention should be drawn to
possible differences
In Table 2 and 3, the numbers in the MM don’t match – 37 or 38?.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests