Measurement Issues in Trials of Pediatric Acute Diarrheal Diseases: A

Systematic Review
Bradley C. Johnston, Larissa Shamseer, Bruno R. da Costa, Ross T. Tsuyuki and
Sunita Vohra
Pediatrics 2010;126;e222; originally published online June 21, 2010;
DOI: 10.1542/peds.2009-3667

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Measurement Issues in Trials of Pediatric Acute
Diarrheal Diseases: A Systematic Review
abstract
BACKGROUND: Worldwide, diarrheal diseases rank second among
conditions that afict children. Despite the disease burden, there is
limited consensus on how to dene and measure pediatric acute diar-
rhea in trials.
OBJECTIVES: In RCTs of children involving acute diarrhea as the pri-
mary outcome, we documented (1) how acute diarrhea and its resolu-
tion were dened, (2) all primary outcomes, (3) the psychometric prop-
erties of instruments used to measure acute diarrhea and (4) the
methodologic quality of included trials, as reported.
METHODS: We searched CENTRAL, Embase, Global Health, and Medline
from inception to February 2009. English-language RCTs of children
younger than 19 years that measured acute diarrhea as a primary
outcome were chosen.
RESULTS: We identied 138 RCTs reporting on 1 or more primary out-
comes related to pediatric acute diarrhea/diseases. Included trials
used 64 unique denitions of diarrhea, 69 unique denitions of diar-
rhea resolution, and 46 unique primary outcomes. The majority of
included trials evaluated short-term clinical disease activity (incidence
and duration of diarrhea), laboratory outcomes, or a composite of
these end points. Thirty-two trials used instruments (eg, single and
multidomain scoring systems) to support assessment of disease ac-
tivity. Of these, 3 trials stated that their instrument was valid; however,
none of the trials (or their citations) reported evidence of this validity.
The overall methodologic quality of included trials was good.
CONCLUSIONS: Even in what would be considered methodologically
sound clinical trials, denitions of diarrhea, primary outcomes, and
instruments employed in RCTs of pediatric acute diarrhea are hetero-
geneous, lack evidence of validity, and focus on indices that may not be
important to participants. Pediatrics 2010;126:e222e231
e222 JOHNSTON et al
Downloaded from pediatrics.aappublications.org at Health Internetwork on November 3, 2011
AUTHORS: Bradley C. Johnston, PhD,a Larissa Shamseer,
+
MSc,b Bruno R. da Costa, MSc,c Ross T. Tsuyuki, PharmD,
MSc,d,e and Sunita Vohra, MD, MScb,e
aDepartment of Clinical Epidemiology and Biostatistics,
McMaster University, Health Sciences Centre, Hamilton, Ontario,
Canada; bCARE Program, Department of Pediatrics, and
dEPICORE Centre, Department of Medicine, Edmonton General
Hospital, University of Alberta, Edmonton, Alberta, Canada;
cInstitute of Social and Preventive Medicine, University of Bern,
Bern, Switzerland; and eSchool of Public Health, University of
Alberta, Edmonton, Alberta, Canada
KEY WORDS
randomized trials, pediatrics, acute diarrhea, denitions,
outcomes
ABBREVIATIONS
PADpediatric acute diarrhea
RCTrandomized, controlled trial
CENTRALCochrane Central Register of Controlled Trials
WHOWorld Health Organization
Dr Johnston participated in screening, data extraction, and
quality assessment of articles, completed the analysis,
interpreted the results, and drafted the manuscript; Ms
Shamseer participated in screening, data extraction, and quality
assessment; Mr daCosta participated in screening articles for
eligibility and data analysis; Drs Tsuyuki and Vohra participated
in the design of study and interpretation of the results; and all
authors critically revised the article and approved the version to
be published.
www.pediatrics.org/cgi/doi/10.1542/peds.2009-3667
doi:10.1542/peds.2009-3667
Accepted for publication Mar 9, 2010
Address correspondence to Bradley C. Johnston, PhD,
Department of Clinical Epidemiology and Biostatistics, McMaster
University, Health Sciences Centre 2C12, 1200 Main St W,
Hamilton, Ontario, Canada L8N 3Z5. E-mail: bjohnst@mcmaster.
caAccepted for publication Mar 9, 2010
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2010 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.

Acute diarrhea in children is a com-
mon and potentially serious condition
with global signicance. Pediatric
acute diarrhea (PAD) presents as a
change in normal bowel habit includ-
ing a substantial increase in the fre-
quency of bowel movements and/or a
decrease in stool consistency. The de-
gree of change can be related to the
childs age and nutritional status and
the underlying cause of diarrhea. The
most common cause of acute diarrhea
involves gastrointestinal infection.1 Al-
though diarrhea acts as a defense
mechanism in the body, quickly elimi-
nating infective organisms, the most
serious sequelae is dehydration, par-
ticularly in malnourished or immuno-
suppressed children.2
In 2002, diarrheal diseases ranked
second among conditions that afict
children.3 The cost per diarrheal epi-
sode in the United States has been es-
timated at US $289 in the 36-month-
old ambulatory population.4 The cost of
the 136 000 diarrhea-associated hospi-
talizations that occur annually among
children younger than 5 years is esti-
mated at US $480 million, or a median
cost of US $3586 per case. Of the 136 000
cases, 59 600 (44%) are a result of rota-
virus.5 The total cost to England and
Wales for treating rotavirus-specic
cases in the same age group is esti-
mated at 14.8 million annually (13.3
16.0 million).6 With respect to the global
burden of disease for rotavirus diarrhea
in children younger than 5 years, there
are an estimated 25 million clinic visits, 2
million hospitalizations, and 600 000
deaths worldwide.7
Although the pathophysiology, etiolo-
gies, and clinical sequelae of acute di-
arrhea have been well described in re-
cent years,1 there seems to be limited
consensus on denitions, primary
outcomes, and measurement of PAD in
clinical trials. The denitions of acute
diarrhea have varied in surveillance
studies and clinical trials, which
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makes the incidence of diarrhea dif-
cult to estimate. 8,9 Indeed, few studies
have been performed to address the
choice of outcomes for clinical trials,
and in most pediatric subspecialties,
no research has been conducted.10 In
recognizing the importance of stan-
dard denitions (trial-entry criteria,
diarrhea-resolution criteria) for pri-
mary outcomes, as well as valid and
reliable instruments for evaluating
primary outcomes when planning a
PAD study, our aim was to systemati-
cally assess how diarrhea is dened
and measured in randomized, con-
trolled trial (RCTs) of PAD.
METHODS
Search Strategy
In RCTs of children that involved acute
diarrhea as the primary outcome, we
aimed to document (1) how acute diar-
rhea and its resolution were dened,
(2) all primary outcomes, (3) the psy-
chometric properties of the instru-
ments used to measure acute diar-
rhea, and (4) the methodologic quality
of included trials, as reported. In con-
sultation with an expert health ser-
vices librarian, a systematic review
was performed of 4 major databases
published in English from inception to
February 2009. We searched Ovids
Embase (1980 2009), Medline (1966
2009), CENTRAL (2008, issue 4), and form, 2 reviewers (Dr Johnston and Ms
Global Health (19732009). Search
terms included extensive controlled
vocabulary and key-word searches for
(randomized, controlled trials) and
(anti-diarrheal treatment or prophy-
laxis, eg, oral rehydration, vaccine,
zinc) and (pediatric) and (diarrhea).
There were variations in search terms
depending on the specic indexing of
each database. To identify additional ar-
ticles that used or supported the devel-
opment of measurement instruments,
we searched the bibliographies of in-
cluded RCTs that used an instrument re-
lated to the measurement of PAD. The
REVIEW ARTICLES
search strategy for each database can
be found in Supplemental Appendix S1
(see also Supplemental Appendix S2).
Study Selection
We included studies that (1) were RCTs
(treatment or prophylaxis), (2) were
published in English, (3) covered only
the pediatric population (0 18 years),
(4) were of any intervention (eg, oral
rehydration, probiotic, vaccine), and
(5) included an explicit statement that
the primary outcome was acute diar-
rhea or an a priori sample-size calcu-
lation based on acute diarrhea. For ex-
ample, we accepted statements such
as the sample size was estimated to
give a power of 90% ( 5%) to detect
a 15% reduction in the incidence of
diarrhea as indicative of the studys
primary outcome.11 Searches were
screened by using the titles of articles
and, when available, abstracts. The full
texts of the selected articles were re-
trieved, and teams of 2 reviewers (Dr
Johnston, Mr daCosta, and Ms Sham-
seer) independently assessed each ar-
ticle for inclusion according to pre-
specied criteria. Interrater reliability
was assessed for inclusion criteria by
using statistics, and disagreement
was resolved by consensus.
Data Extraction
Using a standardized data-extraction
Shamseer) independently extracted
data items including study setting,
type of trial (prevention or treatment),
number and age of children enrolled,
intervention, control, the denition of
diarrhea and diarrhea resolution, the
primary outcome(s), the validity and
reliability of any instrument used to
measure or support the evaluation of
diarrhea outcomes (eg, a stool-
consistencyscoring system for deter-
mining acute diarrhea), and proxy as-
sessments of the methodologic quality
for each trial included.12,13 The deni-
tions of diarrhea and its resolution
e223
TABLE 1 Denitions Used in Review
Terminology Description Examples
Outcome domain A relatively broad aspect of the effect of illness on a child, within which In clinical trials of children that involved the treatment or
an improvement may occur in response to an intervention. In prevention of acute diarrhea, domains may include diarrhea,
general, these domains may not be directly measurable themselves, fever, or dehydration.
so outcomes are selected to assess change within them.
Outcome/end point A measurable variable within an outcome domain. The outcome can be (1) Incidence of diarrhea; (2) duration of diarrhea; (3) time to
measured at a variety of time points, which must be clearly stated fecal clearance of rotavirus
by the authors of clinical trials.
Outcome measure A scale, scoring system, instrument, questionnaire, or other tool used (1) The Diarrheal Disease Index39; (2) Bristol Stool Chart91; (3)
for measuring an outcome. They may be an amalgamation of 1 Kings Stool Chart92
outcome within an outcome domain, such as a score based on a
variety of symptoms. More than 1 outcome measure may be
possible to use to represent change in an outcome.
Adapted from Sinha I, Jones L, Smyth RL, Williamson PR. PLoS Med. 2008;5(4):e96.

were classied into categories on
the basis of 3 key dimensions: fre-
quency; consistency; and duration.14
Measurement properties of studies
that used an instrument to support
outcome assessment were also ex-
tracted regardless of whether the
outcome was the primary end point.
Bibliographies of the RCTs that used
instruments were searched for pre-
vious reports of the instrument in
an attempt to uncover psychometric
evidence and trace the lineage of
their development. Any discrepancies
were noted and resolved by joint re-
view of the items in question.
Data Analysis
For the purposes of this systematic re-
view, data-combining was not appro-
priate or necessary. The terminology
used in our analysis is listed in Table 1.
Descriptive statistics are used to illus-
trate the characteristics of trials for
which acute diarrhea as the primary
outcome(s) was reported.
RESULTS
Our electronic search yielded 3257 ref-
erences (Fig 1). The title and abstract
screening identied 707 potentially el-
igible citations. The chance-adjusted,
between-reviewer agreement on the
application of study inclusion criteria
was good ( 0.87 [95% condence
interval: 0.82 0.91), resulting in the in-
clusion of 138 RCTs. The included RCTs
enrolled 188 760 children. Of the in-
cluded trials, 92 were conducted with
infants and toddlers up to 3 years of
age, 24 with children up to 5 years of
age, 21 with children up to 18 years,
and 1 trial involved children at the
mean age. Forty-three (31%) were pro-
phylaxis trials, and 95 (69%) were
treatment trials. Forty-six (33%) trials
were community-based studies, 91
(66%) involved treatment in a health
care setting, and 1 was conducted in
both settings. Interventions were di-
verse and involved 34 therapies (alone
or in combination, see Table 2). Using
the Jadad 0-to-5 scale, based on the
reports of the included RCTs, the me-
dian methodologic quality was 3.0
(range: 15). Concealment of alloca-
tion was adequate in 61 (44%) of the
trials, inadequate in 1 trial, and un-
clear in the remaining 76 (55%) trials.
Denitions of Diarrhea and Its
Resolution
The authors reported a denition of di-
arrhea (onset) for 132 (96%) trials. For
64 (46%) of the trials, a unique and in-
dependently distinguishable denition
of diarrhea (ie, inclusion criteria for
treatment trials, diagnostic criteria
for prophylaxis trials) was reported.
The denitions of diarrhea were clas-
sied into 10 categories on the basis of
frequency, consistency, and duration
or stool output (mL/kg per hour).
Forty-three (33%) trials used a varia-
tion of the World Health Organization
(WHO) denition of diarrhea, although
most reports did not refer explicitly to
the WHO denition2 (see Table 3). Seven
(5%) of the studies operationalized di-
arrhea on the basis of the mothers
perception.1521
One hundred three studies (75%)
provided a denition of diarrhea res-
olution (offset), 69 (50%) of which
provided a unique description of res-
olution. Of the 70 unique denitions,
27 provided 3 criteria (frequency,
consistency, duration), 18 provided 2
criteria, and 24 provided 1 criterion.
Ten of the 24 studies that provided
just 1 criterion used a previously
validated denition of diarrhea resolu-
tion (ie, 3 intervening diarrhea-free
days).11,20,2229 The Barreto et al (1994)
study was the only one that cited the
previous validity report of the deni-
tion of diarrhea resolution.11,30
Primary Outcomes
Eighty-seven (63%) studies explicitly
reported 1 or more primary outcomes,
112 (81%) provided a statement re-
garding a sample-size calculation, and
61 (44%) trial reports clearly stated
both the primary outcome(s) and a
statement regarding sample size.
These trials included 46 uniquely dif-
ferent primary outcomes; none of
them reported the use of a valid and

e224 JOHNSTON et al
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 REVIEW ARTICLES

4410 potentially relevant

titles/abstracts

1153 duplicates

3257 articles titles/abstracts screened

2550 nonrelevant

707 articles for full text review

1 nonretrievable

568 excluded
Reasons for exclusion:
314 primary outcome not PAD
137 not an RCT
57 trials not exclusive to children
37 duplicates
23 non-English

138 articles included

(estimated = 0.868)
FIGURE 1
Flow diagram of search results.

reliable primary outcome or instru-
ment for evaluating the primary out-
come. For the majority of primary out-
comes, the following domains were
evaluated: clinical disease activity, lab-
oratory outcomes, or a composite of
these domains. The most common pri-
mary outcomes evaluated involved
short-term clinical disease activity
(duration of diarrhea in 72 trials and
incidence of diarrhea in 48 trials) (see
Table 4 for details).
Reliability of Instruments for
Supporting Outcome Evaluation
Thirty-two trials (23%) used instru-
ments to assess diarrheal disease ac-
tivity,11,15,16,19,25,3158 of which 18 trials

TABLE 2 Interventions TABLE 3 Denitions

Most Common Interventions No. of Denition of Diarrhea (Onset) No. of
Administered Trials Trials
Oral rehydration 32 2 loose or liquid stools in 24 h 2
Probiotic 22 3 loose or watery or liquid or semiliquid stools in 24 h (WHO criteria)a 43
Zinc 18 3 loose/unformed/diarrhea stools in 24 h or 1 blood or mucoid stool in 24 hb 15
Vitamin A 10 3 loose/watery stools in 48 h 3
Zinc and supplement(s) 9 4 loose/unformed/watery/liquid stools in 24 h 13
Vaccine 9 5 loose/watery/liquid in 24 h 8
Formula 8 Mothers judgment with or without criteria (eg, 3 loose/watery stools in 24 h) 7
Zinc and vitamin A 5 Gastroenteritis (4 criteria, 1 of which was 3 loose/watery stools in 24 h) 4
Antibiotic 4 Trials having dened diarrhea by using 1 or 2 criteria (and not tting into the categories above)c 35
Colostrum 3 Dened diarrhea as stool output/purging rate in mL/kg per h 2
Homeopathy 3 a To meet WHO criteria, study reports must have stated liquid or watery to be included and must have not stated anything
Loperamide 2 about blood or mucus.
b Did not contain the term liquid or watery and/or contained the term blood or mucous. Two of the 15 trials used a
Prebiotic 2
previously validated denition: 3 loose stools or 1 bloody stools in 24 hours.22,30,93
Smectite 2 c By comparison, the other studies always used frequency and consistency over a prespecied time period.

PEDIATRICS Volume 126, Number 1, July 2010 e225

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TABLE 4 Primary Outcomes Evaluated in the Trials tion of diarrhea.* Only 1 study report
Domain/Subdomain and Outcome No. (%) of Trials That stated the reliability properties of
Evaluated the a stool-consistencyscoring scheme
Primary Outcome
used to support the measurement of
Clinical disease activity
Diarrhea
the chosen primary outcome measure
Diarrhea duration 72 (52) (duration of diarrhea) and provided a
Diarrhea incidencea 48 (35) citation for the results of a reliability
Stool output 46 (33) study that supported their instrument
Stool frequency 12 (9)
Intake 5 (4)
choice.31
Stool consistency 2 (1)
Validity of Instruments
Rate of unresolved diarrhea 2 (1)
Clinical cureb 2 (1) Of the 32 trials that used instruments,
Proportion of patients recovered at 48 h 1 8 used 1 of 3 multidomain (eg, diar-
Rating of efcacy/acceptability (by guardian) 1
Duration of relief 1
rhea, fever, dehydration) instruments:
Vomiting the 15-point modied Diarrheal In-
Vomiting frequency 2 (1) dex Score; the 20-point Ruuska and
Vomiting duration 1 Vesikari Score; and a 24-point instru-
Dehydration: dehydration on day 3 1
ment proposed by Clark et al58 in 1988.
Fever
Fever incidence 2 (1) The authors did not report the mea-
Fever duration 3 (2) surement properties of these instru-
Weight: weight change 4 (3) ments.34,35,39,42,43,48,51,55 However, Block
Growth: length 1
Laboratory
et al35 stated that the 24-point clinical
Entamoeba histolytica duration 2 (1) scoring system that they used was val-
Ascaris lumbricoides duration 1 idated and cited Clark et al.58 In retriev-
Giardia lamblia duration 2 (1)
ing the full text of this article and any
Escherichia coli duration 1
Giardia lamblia prevalence 2 (1) related articles cited by Clark et al, no
Entamoeba histolytica prevalence 2 (1) articles contained a report of the mea-
Ascaris lumbricoides prevalence 1 surement properties of the 24-point
Escherichia coli prevalence 1
Absence of Shigella spp 2 (1) instrument.5860
Time to fecal clearance of rotavirus 2 (1) Two additional trial reports stated that
Reducing substances 1
Serum electrolyte 1
their instrument was valid.16,25 The in-
Functional status struments included a chart with pic-
No. of childcare center absences 1 ture symbols to record the frequency
Health resource utilization
of diarrhea stools25 and a question-
Hospitalization 3 (2)
Hospital stay (duration) 1 naire on the number, consistency, and
No. of clinic visits 1 presence of blood or mucus in stools.16
No. of antibiotic prescriptions 1 The former cited an unpublished arti-
Treatment sought 1
Adverse events associated with therapy cle in support of its claims of valida-
Diarrhea 1 tion,25 whereas the latter provided no
Vomiting 1 citation to support claims of validity
Compositesc
Gastroenteritis 6 (4)
for the questionnaire used.16
Other 3 (2) With respect to the additionally identi-
a Five diarrhea-incidence outcomes are a composite of diarrhea with or without visible blood, mucus, or positive microbial ed multidomain instruments (the 20-
assay results (eg, Clostridium difcile, G lamblia).
b Cessation of watery stools within 48 hours of start of the study drug. point Ruuska and Vesikari Score, 15-
c Diarrhea with or without rotavirus antigen detection, visible blood/mucus, electrolyte abnormalities, abdominal pain,
point Diarrheal Index Score), we also
vomiting, weight gain, dehydration, need for rehydration, or hospitalization.
searched for previous reports of these
instruments and collected the full-text
articles in an attempt to trace the lin-
(15%) used an instrument to evaluate stool-consistency instruments were
stool-consistency categories (some applied to determine primary out- * Refs 15, 25, 3133, 38, 39, 41, 44 47, 49, 52, 53, 54,
with accompanying pictures). These comes such as the incidence or dura- 56, and 57.

e226 JOHNSTON et al
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eage of their development.6169 We
were unable to locate any reports that
described the psychometric proper-
ties of these instruments.
The uniformity of instrument selection in
trials that examined vaccines for the
prevention of acute infectious diarrhea
(rotavirus gastroenteritis) seems to be
superior to that of other included tri-
als. Specically, 7 of 9 vaccine tri-
als34,35,42,43,48,51 included for review used
either the 20- or 24-point scoring sys-
tems cited above. The ability of these
instruments to distinguish the severity
of illness68 and to be responsive to
change in multiple RCTs provides some
reassurance of their validity.
DISCUSSION
Worldwide, acute diarrheal diseases
rank second among conditions that af-
ict children, yet there is surprisingly
little agreement (or validity) on the
denition and measurement of this im-
portant illness. We identied 138 RCTs
from which 64 unique denitions of di-
arrhea, 69 unique denitions of diar-
rhea resolution, and 46 unique pri-
mary outcomes were reported. The
large majority of included trials evalu-
ated short-term clinical disease activ-
ity, laboratory outcomes, or a compos-
ite of these 2 end points. Thirty-two
trials used instruments to support
short-term disease-activity evaluation,
the reports for 3 of which stated that
the instrument used was valid.16,25,35
However, for none of the trials (or their
citations) was evidence of their valida-
tion reported. Given our results, future
trial designers should consider evalu-
ating primary outcomes that may be
considered of greater patient impor-
tance (functional status, health-
related quality of life).70 In addition,
given the heterogeneous denitions
and apparent lack of valid instruments
for evaluating PAD, conduct of mean-
ingful comparative-effectiveness trials
is limited and the opportunity to carry
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out and interpret knowledge synthesis
(eg, meta-analysis) is impeded.
Aside from a single stool-consistency
scoring system, previously shown to
be reliable,31 the majority of instru-
ments used either are currently un-
published or no citation regarding
their development or measurement
properties has been provided. If we
consider the importance of a reliable
instrument in the measurement of di-
arrhea incidence or duration, the con-
sistency of stool (formed versus loose
versus liquid) is a pivotal discrimina-
tor for determining the incidence of di-
arrhea (number of diarrhea stools in
the preceding 24 hours) and its reso-
lution (duration of diarrhea). Without a
reliable instrument to support what is
and is not considered diarrhea (such
as the Stool Consistency Classication
System),71 interrater variation alone
has the potential to make the dif-
ference between an intervention
that demonstrates therapeutic signi-
cance and no response, and between
registered US Food and Drug Adminis-
tration approval and no approval.72
There has been almost no research on
denitions of diarrhea, primary out-
comes, and instruments used in stud-
ies of acute diarrhea. In addition, few
reviews in the eld of pediatrics have
used the comprehensive review meth-
ods we have used.10 A previous review
of Medline and CINAHL (Cumulative In-
dex to Nursing and Allied Health Liter-
ature) (19912002) identied 29 ob-
servational studies of adults enrolled
in tube-feeding studies. Authors of the
included studies reported 22 unique
denitions of diarrhea and 4 different
outcomes.14 Although we are unaware
of other reviews of acute diarrheal out-
comes used in clinical trials of chil-
dren, we are aware of at least 4 re-
views that involved end points used
with other pediatric conditions. Sinha
et al73 (2009) conducted a review of
CENTRAL (1988 2007) for clinical trials
REVIEW ARTICLES
of inhaled corticosteroids in children
with chronic asthma to determine
which primary and secondary out-
comes had been measured, whether
all relevant domains were repre-
sented, and whether there was consis-
tent selection of outcomes within
these domains. Anand et al74 (2005)
searched Medline, Embase, and the Co-
chrane registry (from inception to
2003) for review articles or original
data related to infant pain, ethical is-
sues, and study design (including mea-
surement instruments); Miller et al75
(2001) searched PubMed (1966 2000)
for all prospective therapeutic trials of
adult and juvenile idiopathic inamma-
tory myopathies for disease-specic
instruments and the publication of
studies to support the validation of
these instruments; and Zhang and
Schmidt76 (2001) searched 5 leading
general medicine and pediatric jour-
nals (19931998) for primary out-
comes used to evaluate therapies in
RCTs of newborn infants. To our knowl-
edge, our study represents the most
comprehensive review, using indepen-
dent reviewers, of denitions, primary
outcomes, and instruments used in pe-
diatric RCTs and, in particular, RCTs of
PAD.
Our results may be limited as a prod-
uct of not searching the gray literature
(contact with authors or review of all
citations of included studies). How-
ever, our aim was not to identify every
RCT of PAD published to obtain a cumu-
lative point estimate around the ef-
cacy of interventions through meta-
analysis. Rather, we aimed to acquire a
comprehensive sample of PAD trials
for evaluation. Another potential limi-
tation is the exclusion of nonEnglish-
language studies, which may have
used validated outcomes or instru-
ments. Given the large amount of liter-
ature in this area, to make the study
feasible we needed to build in some
limitations that were reasonable. We
e227
did not search nonEnglish-language
studies, because we were interested in
identifying denitions, primary out-
comes, and validated instruments in
English. There is reason to suppose
that even if something existed in an-
other language, one could not assume
it was valid in its English format with-
out additional validation.77 An addi-
tional limitation of our methods was
the use of the Jadad scale for quality
assessment of trials. The scale has 2
major drawbacks: it does not include
all items that have been empirically
shown to be associated with risk of
bias, and it assigns weights to differ-
ent items in the scale that are not ad-
equately supported by empirical evi-
dence. Given these limitations, it is
preferable to use an instrument such
as the Risk of Bias tool, which contains
additional items associated with bias
and does not provide an overall score
per trial.78 The use of the Jadad scale
would be of particular concern if we
had elected to use its score for eligibil-
ity criteria in a meta-analysis or to con-
duct subgroup analyses.79,80 However,
our objective was to employ a widely
used proxy measure of quality assess-
ment, with empirically supported
items, to provide a general description
of our sample.
The heterogeneity among RCTs of PAD
identied here is an example of issues
that are important across all trials and
meta-analyses. We were surprised to
nd that these issues have not been
resolved in a condition of such high
public health importance. Given the di-
versity of diarrheal denitions, pri-
mary outcomes, and instruments re-
ported, there is a need to come to
consensus in at least 3 key areas: (1)
standard denitions of diarrhea and
diarrhea resolution; (2) standard core
outcomes that consider important pa-
tient or parent end points; and (3) in-
struments to support core outcomes
that are valid and reliable. Such an ef-
e228 JOHNSTON et al
Downloaded from pediatrics.aappublications.org at Health Internetwork on November 3, 2011
fort would require consensus, guide-
lines, and adherence on behalf of the
relevant stakeholders. Collaborative
efforts in other research elds have
led the charge on this important, but
often neglected, issue. Perhaps the
best example is the Outcome Mea-
sures in Rheumatoid Arthritis Clinical
Trials (OMERACT) initiative, with which
a group of rheumatology investigators
have paved the way toward standard-
izing the conduct, assessment, and re-
porting of outcomes in clinical trials in
their eld.81,82 Standard criteria (de-
nitions, outcomes) in future trials are
not meant to impede the development
or use of other criteria but would rep-
resent criteria routinely used and re-
ported. Investigators who wish to use
other criteria in a particular trial
should be encouraged to do so, but
when reporting the results of
their trial, selective reporting could
be avoided (outcome-reporting bias)
through reporting of core criteria that
the international diarrhea-research
community have endorsed.83,84
As a result of the heterogeneous de-
nitions and outcomes and the lack of
validity and reliability evidence for the
instruments identied here, the com-
bining of trials of PAD by using meta-
analysis techniques may be mislead-
ing. If the same systematic biases, in
this case measurement error, are im-
bedded across a series of trials, meta-
analysis would simply reinforce these
biases to produce spurious statistical
stability and, in so doing, may discour-
age further research.85 Standard de-
nitions and core outcomes, each with
appropriate psychometric evidence of
reliability and validity, would repre-
sent an important advance and help
avoid misleading results as a product
of pooling RCTs of PAD.
The basic principles of RCT design em-
phasize the importance of randomiza-
tion, allocation concealment, blinding,
and loss to follow-up.12,13 However, the
importance of using valid and reliable
instruments has been relatively over-
looked by key organizations such as
funders and journals that endorse
guidelines for the reporting of trials
and systematic reviews of trials86,87
(see Supplemental Appendix S3). To
ask more sophisticated research
questions, head-to-head (comparative-
effectiveness) trials that use factorial
or noninferiority trial designs are
needed. Comparative-effectiveness tri-
als need to also use valid and reliable
instruments.88 For instance, although
oral rehydration solution (ORS) and
vaccines have had an enormous im-
pact worldwide in reducing the num-
ber of deaths related to diarrhea, it is
unclear which ORS may be the most
benecial. Given that there are thera-
pies known to substantially reduce
morbidity and mortality rates, there is
now a need for head-to-head compar-
ative trials (ie, glucose-based ORS ver-
sus rice-based ORS) to elucidate the
most effective therapies for treating
PAD. In addition, these trials are essen-
tial for establishing the clinical impact
that emerging interventions such as
probiotics or zinc may have.89,90 Al-
though placebo-controlled trials have
demonstrated that probiotics as an
adjunct to ORS may reduce the dura-
tion of diarrhea,89 it is not clear which
probiotic strain may be the most
effective. Head-to-head comparative-
effectiveness trials, and systematic re-
views that attempt to synthesize this
information, would benet from valid,
reliable outcomes. Finally, the design-
ers of future trials should consider us-
ing primary outcomes that have been
established as important to parents
and children.
ACKNOWLEDGMENTS
Dr Johnston receives salary support
from the SickKids Foundation, and Dr
Vohra receives salary support from
the Alberta Heritage Foundation for
Medical Research.

We thank Linda Slater and Soleil
Surette (research librarians) and Dr
Richard Fedorak (gastroenterologist)
for valuable input toward the search
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e231
 Measurement Issues in Trials of Pediatric Acute Diarrheal Diseases: A
Systematic Review
Bradley C. Johnston, Larissa Shamseer, Bruno R. da Costa, Ross T. Tsuyuki and
Sunita Vohra
Pediatrics 2010;126;e222; originally published online June 21, 2010;
DOI: 10.1542/peds.2009-3667
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/126/1/e222.full.h
tml
Supplementary Material Supplementary material can be found at:
http://pediatrics.aappublications.org/content/suppl/2010/06/24
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