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\begin{document}

\title{Effects of exercise-based pulmonary rehabilitation on children with
asthma:a systematic review and network meta-analysis}



\author[1]{Jing Jiang}%
\author[1]{Dong Zhang}%
\author[2]{Yapan Huang}%
\author[1]{Zhenguo Wu}%
\author[1]{Wei Zhang}%
\affil[1]{Henan University of Chinese Medicine}%
\affil[2]{Nanyang Zhang Zhongjing Hospital Nanyang 473007 China}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Objective:} This systematic review aimed to systematize
different designs of exercise-based pulmonary rehabilitation (PR) for
children with asthma and explore which designs are optimal.
\textbf{Methods:} PubMed, EMBASE, Cochrane Library, Web of Science Core
Collection and MEDLINE were searched up until April 01, 2021, which was
conducted for any relevant randomized controlled trials (RCTs) of
exercise-based PR in childhood asthma. Language is limited to English.
Network meta-analyses and standard meta-analyses were performed using
STATA (version 16.0), quality analyses were performed using RevMan
(version 5.3). \textbf{Results:} A total of 24 RCTs involving 1031
patients were included. 14 studies were endurance training, which was
the most commonly used form of exercise, and 7 studies rehabilitation
sites were conducted in hospitals. A network meta-analysis showed that
compared with other forms of exercise, interval training significantly
improved the PAQLQ (Pediatric Asthma Quality of Life Questionnaire),
including activity scores {[}MD=3.02, 95\% CI (1.74,4.30){]}, symptom
scores {[}MD=2.68, 95\% CI (2.04,3.32){]}, emotional scores {[}MD=2.47,
95\% CI (0.91,4.03){]}, and total scores {[}MD=2.68, 95\% CI
(1.79,3.57){]}. Interval training {[}MD=188.97, 95\% CI (-59.27,
437.21){]} also had a more significant effect on the 6MWT (6-minute walk
test). No adverse events were found in this study. Exercise training had
no significant effect on FEV \textsubscript{1}(the forced expiratory
volume at 1s to predicted value ratio) {[}WMD=0.59, 95\% CI (-2.00,
3.19){]}, however, the combined of endurance training and respiratory
training was found to significantly improve both FVC (the forced vital
capacity to predicted value ratio) {[}MD=5.37, 95\% CI (0.07,10.67){]}
and FEF25-75\% (the forced expiratory flow between 25\% and 75\% of
vital capacity ratio) {[}WMD=11.31, 95\% CI (2.13, 20.48){]}.
\textbf{Conclusions}: Exercise-based PR is a safe and effective for
childhood asthma. Interval training may be a core component of improving
quality of life and exercise capacity in childhood asthma, the
combination of respiratory training and endurance training has
significant effects on lung function.This result should be viewed with
caution, and high-quality RCTs are still needed to confirm its clinical
efficacy,%
\end{abstract}%



\sloppy


\textbf{Effects of exercise-based pulmonary rehabilitation on children
with asthma:a systematicreview and network meta-analysis}

Jing Jiang\textsuperscript{1,2,3}, Dong Zhang\textsuperscript{1,3},
Yapan Huang\textsuperscript{2}, Zhenguo Wu\textsuperscript{1}, Wei
Zhang\textsuperscript{1,2}

1 Henan University of Chinese Medicine, Zhengzhou 450046, China

2 Nanyang Zhang Zhongjing Hospital, Nanyang 473007, China

3 Department of Respiratory Diseases, The First Affiliated Hospital of
Henan University of Chinese Medicine, Zhengzhou, Henan 450003, China

\textbf{Correspondence:} Wei Zhang

\textbf{Address:} Nanyang Zhang Zhongjing Hospital, Nanyang,1888,
Xuefeng West Road, Nan yang, He nan, 473008, China

\textbf{Tel:} 0377-83976200

\textbf{Fax:} 0377-83976200

\textbf{Email:} 13838966395@163.com

\textbf{Abstract}

\textbf{Objective:} This systematic review aimed to systematize
different designs of exercise-based pulmonary rehabilitation (PR) for
children with asthma and explore which designs are
optimal.\textbf{Methods:} PubMed, EMBASE, Cochrane Library, Web of
Science Core Collection and MEDLINE were searched up until April 01,
2021, which was conducted for any relevant randomized controlled trials
(RCTs) of exercise-based PR in childhood asthma. Language is limited to
English. Network meta-analyses and standard meta-analyses were performed
using STATA (version 16.0), quality analyses were performed using RevMan
(version 5.3). \textbf{Results:} A total of 24 RCTs involving 1031
patients were included. 14 studies were endurance training, which was
the most commonly used form of exercise, and 7 studies rehabilitation
sites were conducted in hospitals. A network meta-analysis showed that
compared with other forms of exercise, interval training significantly
improved the PAQLQ (Pediatric Asthma Quality of Life Questionnaire),
including activity scores {[}MD=3.02, 95\% CI (1.74,4.30){]}, symptom
scores {[}MD=2.68, 95\% CI (2.04,3.32){]}, emotional scores {[}MD=2.47,
95\% CI (0.91,4.03){]}, and total scores {[}MD=2.68, 95\% CI
(1.79,3.57){]}. Interval training {[}MD=188.97, 95\% CI (-59.27,
437.21){]} also had a more significant effect on the 6MWT (6-minute walk
test). No adverse events were found in this study. Exercise training had
no significant effect on FEV\textsubscript{1}(the forced expiratory
volume at 1s to predicted value ratio) {[}WMD=0.59, 95\% CI (-2.00,
3.19){]}, however, the combined of endurance training and respiratory
training was found to significantly improve both FVC (the forced vital
capacity to predicted value ratio) {[}MD=5.37, 95\% CI (0.07,10.67){]}
and FEF25-75\% (the forced expiratory flow between 25\% and 75\% of
vital capacity ratio) {[}WMD=11.31, 95\% CI (2.13,
20.48){]}.\textbf{Conclusions} : Exercise-based PR is a safe and
effective for childhood asthma. Interval training may be a core
component of improving quality of life and exercise capacity in
childhood asthma, the combination of respiratory training and endurance
training has significant effects on lung function.This result should be
viewed with caution, and high-quality RCTs are still needed to confirm
its clinical efficacy,

\textbf{Keyword:} asthma, children, pulmonary rehabilitation, network
meta-analysis, Systematic review

\textbf{1.Background}

Asthma in children is a common non-infectious chronic respiratory
disease characterized by episodic and persistent airflow restriction,
with symptoms of wheezing, coughing, chest tightness and shortness of
breath {[}1,2{]}. Asthma has become more common globally in recent
years, which is one of the most important global public health
problems.~It is estimated that around 300 million people suffer from
asthma, and the incidence of asthma is likely to increase as the
proportion of the urban population increases {[}3{]}. The prevalence of
asthma in children (9.5\%) is higher than adults (7.7\%), and women
(9.2\%) higher than men (7.0\%) {[}4{]}. Approximately 157,000 children
hospitalized with asthma and 640,000 emergency room visits are recorded
in the United States {[}5{]}. Asthma negatively affects children's
quality of life, exercise capacity, and lung function, while increasing
family stress and socioeconomic burden {[}6{]}. Treatment goals for
childhood asthma are to minimize the negative impact of these events and
prevent their recurrence.

Currently, \selectlanguage{greek}β\selectlanguage{english}2-agonists and glucocorticoids, as the main drugs for
childhood asthma, are widely used in clinical practice, but most of the
drugs have side effects. Therefore, safer and more effective
interventions are being explored. As a core component of non-drug
therapy, PR is a comprehensive intervention that mainly includes
exercise training, family education, and health education, aiming to
improve the physical and mental health of patients and promote long-term
health {[}7,8{]}. Exercise training as the cornerstone of PR, mainly
including endurance training, resistance/strength training, inspiratory
muscle training, interval training, and neuromuscular electrical
stimulation {[}8{]}, and has been shown to improve asthma symptoms and
severity, quality of life, and lung function {[}9-11{]}. After a search
we found that formal PR programs are very rare in a child environment,
and there is a lack of data describing potential benefits for childhood
asthma, especially whether exercise-based PR can be used as an
adjunctive treatment for childhood asthma. Thus, this systematic review
aimed to systematize the different designs used to provide
exercise-based PR designs for childhood asthma and explore which ones
are the most effective.

\textbf{METHODS}

\textbf{2.1 Search strategy}

The International Register of Prospective Systematic Reviews (PROSPERO)
and the Cochrane Library were searched for no similar studies. The
systematic review protocol is registered on the PROSPERO website
(www.crd.york.ac.uk/Prospero), number CRD42022326995. PubMed, EMBASE,
Cochrane Library, Web of Science Core Collection and MEDLINE were
searched up until April 01, 2021, which was conducted for any relevant
randomized controlled trials (RCTs) of exercise-based PR in childhood
asthma. The language restriction is English.

Taking into account the possible differences between different
databases, the retrieval strategy was adjusted accordingly. Detailed
search strategy and steps can be found in Appendix 1 of the
Supplementary Material. Additionally, we also read citations to relevant
articles retrieved to ensure inclusion.

\textbf{2.2 Inclusion criteria}

Inclusion criteria include the following: (a) Research subjects:
childhood asthma who were under 18 years old. All meet the diagnostic
standard of GINA childhood asthma {[}12{]}, and the sex, race were not
restricted. (b) Intervention: Any exercise-based PR technique, such as
endurance exercise (cycling, running, yoga, basketball, Tai Chi, etc.),
strength training, interval training, etc. (c) Control: conventional
treatment includes medication, standard care, or routine activities
without exercise. (d) Outcome:exercise capacity (measured by 6MWT),
Quality of life indicators (measured by PAQLQ: total score, activity
scores, symptom scores, emotional scores). Lung function (measured by
FEF25-75\% pred, FEV\textsubscript{1}\% pred and FVC\% pred). (e) Type
of study: randomized controlled trial. (f) Language: English only.

\textbf{2.3 Exclusion criteria}

The exclusion criteria include any of the following: (a) Non-English
language studies; (b) Full-text literature that cannot be obtained
through various channels; (c) Participants with pulmonary disease other
than asthma; (d) Conferences, guidelines, reviews, animal experiments;
(e) Non-randomized controlled trials with study designs that were,
retrospective, observational, cohort, and case-control studies.

\textbf{2.4 Study selection}

NoteExpress software was used for research screening. First, two
researchers (J Jiang and ZG Wu) independently screened and checked the
titles and abstracts of articles to exclude duplicate and irrelevant
studies. Second, the full text of potentially eligible studies was
downloaded and reviewed according to the inclusion and exclusion
criteria stated above. Finally, when inconsistencies or disagreements
arose, a third author (W Zhang) assisted in resolving the issue.

\textbf{2.5 Data extraction}

Two authors (J Jiang and D Zhang) independently extracted data and
cross-checked, disagreements were resolved with the help of W Zhang. The
extracted contents included: (a) Basic research information: first
author and publication year; (b) Study characteristics: patient age,
sample size, intervention measures, intervention site, treatment
frequency and treatment time. (c) Outcome measures~were as follows:
6MWT, PAQLQ, FEF25-75\% pred, FEV\textsubscript{1}\% pred and FVC\%
pred.

\textbf{2.6 Quality assessment}

Risk of bias was used the Cochrane Collaboration's risk of bias
assessment tool {[}13{]}. Two authors (J Jiang and YP Huang)
independently rated each study as ``high'', ``low'', ``unclear'' for
risk of bias assessment, W Zhang helped resolve when disagreements were
reached. The evaluation tools mainly include the method of random
allocation sequence, blinding of subjects or trial personnel, blinding
of outcome assessors, completeness of outcome data, selective reporting,
allocation concealment, and other sources of bias.

\textbf{2.7 Data analysis}

All network meta-analyses and standard meta-analyses were performed
using the STATA (16.0 version). Continuous variables were expressed as
weighted MD (WMD) or mean difference (MD), and 95\% confidence intervals
(95\% CI) were calculated. The adjusted indirect comparisons were
performed with MD and 95\% CI to assess the indirect comparisons
different types of exercise PR on childhood asthma quality of life, lung
function and exercise capacity. We conducted a subgroup analysis of FEV1
and FEF25-75\% based on different interventions to reduce heterogeneity
and address potential confounding.

\textbf{Results}

\textbf{Search results}

A total of 10208 studies were retrieved, of which 1877 studies were
replicated. By screening titles and abstracts, 55 studies were
considered potentially eligible. After reading the full text, 24 studies
{[}14-37{]} were finally included (Fig1).

\textbf{3.2 Study characteristics}

The characteristics of the 24 studies are summarized in Table 1. (a)
Study characteristics: A total of 7 interventions are endurance
training; endurance and respiratory training; endurance, resistance and
respiratory training; endurance and strength training; respiratory and
strength training; respiratory training; interval training. A single
training modality included 14 studies {[}15,17,18,21,23,25,26,28,29,
31-33,36,37{]} of endurance training, 2 studies {[}27,35{]} of interval
training, and 1 study {[}24{]} of respiratory muscle training; (b) The
treatment time of the study is different, ranging from the time of up to
4-52 weeks. Most frequent timings to begin intervention were 12 W (n=9)
{[}16,18,23,25,27,29,33,34,37{]}, 6 W(n=6) {[}15,21,22,28,32,36{]}; (c)
Most of the studies treatments frequency are different, from 1 to 6
times per week. Most of the study treatment frequency were 3 times per
week (n=12) {[}14-17,22, 25-27,29,32,36,37{]}. 2 times per week (n=6)
{[}20,21,23,30,31,34{]}. (d) Most studies were conducted in hospital
settings (n=7) {[}14,16-18,23,26,32{]}, followed by patients' home (n=2)
{[}19,33{]}, school (n=2) {[}24,35{]}. Some studies did not mention the
specific location of children's exercise (Table.1).

\textbf{3.3 Risk of bias evaluation}

24 RCTs were evaluated for literature quality. Ten studies reported a
generation of random sequences, one study was a random draw {[}20{]},
six for random number table {[}15,16,18,21,23,34{]}, two for randomized
envelope {[}17,32{]}, one for random sampling {[}33{]}. Of note, four
studies {[}14,15,17,32{]} reported using the allocation concealment and
one study {[}19{]} mentioned double-blinding, the risk of bias
evaluation is summarized in (Fig. 2, 3)

\textbf{3.4.Standard meta-analysis}

\textbf{3.4.1. FEV\textsubscript{1}\%}

15 studies {[}14,17-19,21-23,25,26,30-34,36,37{]} provided numerical
data for the FEV\textsubscript{1}, five comparisons against control were
performed (Fig. 4a). Compared with the conventional treatment, there was
no significant difference: endurance training {[}WMD=-0.05, 95\% CI
(-4.75, 3.66){]}, endurance and strength training {[}WMD=1.00, 95\% CI
(-8.80, 10.80){]}, endurance and respiratory training {[}WMD=0.35, 95\%
CI (-7.32, 8.02){]}, endurance, resistance and respiratory training
{[}WMD=5.19, 95\% CI (-2.38, 12.75){]}, respiratory and strength
training {[}WMD=-2.45, 95\% CI (-8.38, 3.48){]}, endurance and
respiratory training {[}WMD=4.23, 95\% CI (-2.68, 11.14){]}. After
combined analysis, there was no statistical significance between
exercise PR and lung function FEV\textsubscript{1} {[}WMD=0.59, 95\% CI
(-2.0,3.19){]} (Fig. 4b).

\textbf{3.4.2. FEF25-75\%}

7 studies {[}19,21-24,36,37{]} were included in the analysis and three
comparisons with the control group (Fig .5a). Compared with conventional
treatment, endurance and respiratory training {[}WMD=11.31, 95\% CI
(2.13,20.48){]}, endurance training {[}WMD=0.74, 95\% CI (-4.11,
5.58){]}, respiratory and strength training {[}WMD=1.29, 95\% CI
(-13.39,15.97){]}. After combined analysis, FEF25-75\% {[}WMD=4.07, 95\%
CI (-0.62, 8.77){]}, the difference was not statistically significant
(Fig. 5b).

\textbf{3.5. Network meta-analysis}

\textbf{3.5.1. FVC\%}

9 studies {[}18-23,26,31,37{]} were included in the analysis and two
comparisons with the control group (Fig. 6a). 9 pairwise comparison was
included. Endurance training {[}MD=2.93, 95\% CI (0.73, 5.14){]},
endurance and respiratory training {[}MD=5.37, 95\% CI (0.07, 10.67){]}.
The ranking probability of SUCRA sorting chart is from high to low:
endurance and respiratory training, endurance training, conventional
treatment (88.8\%, 59.8\%, 1.4\%), endurance and respiratory training
was superior to endurance training in lung function FVC(Fig. 6b-d).

\textbf{3.5.2 6MWT}

3 studies {[}17,26,27{]} provided 6WMT data for analysis, two
comparisons were made with the control group (Fig. 7a). Compared with
conventional treatment, endurance training {[}MD=2.93, 95\% CI
(0.73,5.14){]}, interval training {[}MD=188.97, 95\% CI (-59.27,
437.21){]}. The ranking probability of SUCRA sorting chart is from high
to low: Interval Training, Endurance Training, Conventional treatment
(82.4\%, 56.9\%, 10.7\%). The results show interval training has a
significant effect on exercise capacity (Fig. 7b-d).

\textbf{3.5.3 PAQLQ}

6 studies {[}15-17,26,27,34{]} provided PAQLQ data for meta-analysis,
four comparisons with the control group (fig. 8a). The four parts of the
PAQLQ: activity scores, symptoms scores, emotional scores, and total
scores were analyzed. Compared with conventional treatment, both
endurance training and interval training improved PAQLQ. Endurance
training was in the activity scores {[}MD=1.32, 95\% CI (0.60,2.03){]},
symptoms scores {[}MD=1.15, 95\% CI (0.78,1.52){]}, emotional scores
{[}MD=1.25, 95\% CI (0.39,2.12){]}, total scores {[}MD=1.16,95\% CI
(0.66,1.66){]}. Interval training was in the activity scores {[}MD=3.02,
95\% CI (1.74, 4.30){]}, symptoms scores {[}MD=2.68, 95\% CI (2.04,
3.32){]}, emotional scores {[}MD=2.47, 95\% CI (0.91 ,4.03){]}, total
scores {[}MD=2.68, 95\% CI (1.79,3.57){]} (fig. 8b-e). The ranking
probability of the SUCRA ranking chart from high to low, activities
scores: endurance training + resistance training + respiratory training,
interval training, endurance training, respiratory training + strength
training, conventional treatment (89.1\%, 79.2\%, 50.1\%, 22.8\%,
8.7\%). Emotional scores: interval training, endurance training,
respiratory training + strength training, conventional treatment,
endurance training + resistance training + respiratory training (96.9\%,
72.8\%, 31.7\%, 24.9\%, 23.8\%). Symptoms scores: interval training,
endurance training, respiratory training + strength training, endurance
training + resistance training + respiratory training, conventional
treatment (100\%, 74.5\%, 30.9\%, 29.7\%, 14.9\%). Total scores:
interval training, endurance training, endurance training + resistance
training + respiratory training, respiratory training + strength
training, conventional treatment (99.9\%, 71.7\%, 36.9\%, 26.5\%,
14.9\%). Comprehensive analysis of PAQLQ interval training superior to
endurance training(8i-m).

\textbf{Discussion}

As a comprehensive intervention measure, PR has good advantages in
relieving patients' clinical symptoms, increasing exercise endurance and
improving quality of life. It is considered as the first-line non drug
therapy for chronic respiratory diseases, and widely used in the
clinical practice of childhood asthma {[}38,39{]}. Exercise training,
the cornerstone of PR, comes in a variety of forms, and it is unclear
which form will have the best effect on childhood asthma. This
systematic review provides a comprehensive overview of the design of
PR-based programs implemented during asthmatic children and explores
which types of exercise are most effective.

Our systematic review was based on 24 RCTs involving 1031 patients with
asthmatic children. The Standard meta-analysis was based on 16 RCTs with
691 patients, and network meta-analysis was based on 13 RCTs with 433
patients. Most studies were conducted in an inpatient setting (29\%) and
the total duration of the intervention ranging from 4-52 weeks.
Endurance training was the most used components, and most of the
interventions included in the studies were combined with endurance
training. Interval training may be a core component of improving quality
of life and exercise capacity in childhood asthma, the combination of
respiratory training and endurance training has significant effects on
lung function. Exercise-based PR is a safe and effective for asthmatic
children. Moreover, exercise-based PR is safe for asthmatic children,
and no serious adverse events have been found.

Lung function, as an important adjustment index for the evaluation,
treatment, and severity monitoring of bronchial asthma, has always been
used for patient-level diagnosis and detection {[}40{]}, and attracted
more attention in the treatment of pediatric. The results showed that
endurance training combine with respiratory training was significantly
better than other forms of exercise in increasing FVC\% pred and
FEF25-75\% pred, but no significant difference were found in FEV1\%
pred. This result may be due to the lack of exercise-based PR studies on
childhood asthma and different degree of asthma, as well as the total
duration of the intervention, the intensity and frequency of exercise
training, etc.

It is reported that exercise can improve cardiorespiratory fitness,
muscle strength, to relieve or control asthma {[}41{]}. Therefore,
improving exercise capacity has a positive effect on children's quality
of life and asthma symptom control. 6MWT is an effective and reliable
method for measuring children's motor ability, which is safe, simple,
and easy to operate {[}42{]}. Study results show that both endurance
training and interval training improve 6MWT in childhood asthma, but
interval training is better. These results support that exercise-based
PR can improve exercise tolerance, which should be treated with caution
because there are few studies included.

Symptoms and quality of life evaluation are important aspects of asthma
control in children. The Children's Asthma Quality of Life Questionnaire
(PAQLQ) has high reliability and can more accurately reflect the quality
of life in children with asthma {[}43{]}. The higher the score, the
higher the quality of life. Six studies were included in the
meta-analysis, exercise-based PR had a positive effect on the PAQLQ
activity domain, emotional domain, symptom domain and total score. It is
worth noting that interval training and endurance training are better
than other forms of exercise, and interval training is the best. The
results show that exercise-based PR can improve the PAQLQ score and
improve the quality of life on childhood asthma.

\textbf{Methodological considerations}

What needs to be affirmed is that this systematic review and
meta-analysis has certain advantages and limitations. So far, this is
the only Network meta-analysis evaluate the effect of exercise-based PR
on childhood asthma, and exercise-based PR includes a larger and richer
literature. Network meta-analysis makes a direct and indirect comparison
of various types of exercise interventions to determine the best type of
exercise. At the same time, our study has some limitations. First, some
studies have small sample size and poor representativeness, which may
lead to inaccurate results. Second, some studies have not clearly stated
the exercise intensity and frequency, which may lead to some differences
in the results. In addition, it is very difficult to use exercise as an
intervention and blind method, which may affect the authenticity of the
results.

\textbf{Conclusions}

Exercise-based PR may be a safe and effective measure for childhood
asthma to improve children's lung function, exercise capacity, and
quality of life. The combination of endurance and respiratory training
seems to be the most effective for improvements on lung function.
Interval training was more effective in improving quality of life and
exercise capacity. Therefore, the effectiveness of exercise-based PR on
childhood asthma control can provide a reference for children's clinical
treatment. However, the site, intensity, duration, and frequency of
exercise interventions varied among included studies, so results may be
controversial. In conclusion, it is necessary to validate large-scale,
higher-quality RCTs in the future.

\textbf{Authors' Contributions}

W Zhang and D Zhang were responsible for conception and design; J Jiang
and ZG Wu were responsible for research screening; J Jiang and D Zhang
were responsible for collection and assembly of data; J Jiang and YP
Huang were responsible for study quality assessment; W Zhang and D Zhang
were responsible for data analysis and interpretation; all authors were
responsible for manuscript writing and final approval of manuscript. J
Jiang and D Zhang contributed equally to this work and should be cofirst
authors.

\textbf{Conflict of interest}

None declared.

\textbf{Data availability statement}

The data that supports the findings of this study are available in the
supplementary material (References) of this article

\textbf{Acknowledgments}

Thanks to Henan University of Traditional Chinese Medicine for help.

\textbf{References}

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\end{enumerate}

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\verb`Graphical Abstract.docx`  available at \url{https://authorea.com/users/489722/articles/573335-effects-of-exercise-based-pulmonary-rehabilitation-on-children-with-asthma-a-systematic-review-and-network-meta-analysis}

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\verb`Figures.doc`  available at \url{https://authorea.com/users/489722/articles/573335-effects-of-exercise-based-pulmonary-rehabilitation-on-children-with-asthma-a-systematic-review-and-network-meta-analysis}

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\verb`Table.docx`  available at \url{https://authorea.com/users/489722/articles/573335-effects-of-exercise-based-pulmonary-rehabilitation-on-children-with-asthma-a-systematic-review-and-network-meta-analysis}

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