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Mobile Application Interventions and Weight Loss in Type 2 Diabetes: A Meta‐

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DOI: 10.1002/oby.22715

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Original Article Obesity
CLINICAL TRIALS AND INVESTIGATIONS

Mobile Application Interventions and Weight Loss in Type

2 Diabetes: A Meta-Analysis
1,*, 2,*,
Xue Cai Shanhu Qiu Dan Luo1, Limin Wang1, Yanhu Lu1, and Mingzi Li1

Objective: This meta-analysis aimed to assess the effect of mobile

­application (app) interventions on weight loss in patients with type 2 Study Importance
diabetes. What is already known?
Methods: Electronic databases were searched for randomized controlled
►
Weight control is a cornerstone in
trials examining the use of mobile app interventions with outcomes on the management of type 2 diabetes.
weight loss evaluated by body weight or other measures such as BMI Although face-to-face tailored or super-
or waist circumference. A random-effects model was applied to obtain vised lifestyle modification programs fa-
weight mean differences and 95% CIs. cilitate weight loss, they are burdensome
and time consuming.
Results: Fourteen studies enrolling 2,129 patients with type 2 diabetes
►
Mobile applications have emerged
were included. Mobile app interventions could significantly reduce body as a promising tool for diabetes self-
weight (weight mean difference, −0.84 kg; 95% CI: −1.51 to −0.17 kg) management in recent years and have
and lower waist circumference (−1.35 cm; 95% CI: −2.16 to −0.55 cm) proven to be effective in improving gly-
but may not decrease BMI (−0.08 kg/m2; 95% CI: −0.41 to 0.25 kg/m2). cemic control. However, the association
The reductions appeared to be more pronounced in patients with obesity with weight loss in patients with type 2
diabetes is not fully outlined.
or among studies using mobile app interventions combined with other
behavior components. However, weight loss was not moderated by the What does this study add?
functionalities of the mobile apps (all Pinteraction > 0.05) or by the interven- ► Mobile application interventions reduce
tion duration (all P > 0.87). body weight and waist circumference in
Conclusions: Mobile app interventions lead to weight loss in patients with patients with type 2 diabetes, especially
type 2 diabetes and are worth recommending for weight loss promotion. in those with obesity.
► Mobile application interventions com-
Obesity (2020) 0, 1-8. bined with other behavior compo-
nents  lead to a larger magnitude of
weight loss. However, the mobile appli-
cation functionalities do not moderate
Introduction weight loss significantly.

Weight control has been considered a cornerstone in the management of type 2 diabetes. How might these results change the
The latest evidence has suggested that weight loss of more than 5% in the first year follow- focus of clinical practice?
ing diabetes diagnosis is associated with a reduced 10-year risk of cardiovascular events
by 48% (1). Moreover, a 2016 meta-analysis by Zomer et al. (2) pointed out that weight ► Mobile application interventions can be
loss, even at a mild magnitude (that is, less than 2.5%), could improve glycemic control incorporated into clinical practice to pro-
and lower blood pressure in patients with type 2 diabetes. mote weight loss for patients with type 2
diabetes.
Face-to-face tailored or supervised lifestyle modification programs with emphases on
healthy diet and sufficient physical activity have been shown to be effective in facilitat-
ing weight loss (3-5). However, these programs are burdensome and time consuming.
Moreover, the lack of sufficient medical resources and adequate time for frequent visits
may further limit their successful implementation (6). Mobile applications (apps), which
can be installed on any mobile phone and accept data as well as provide professional
feedback to patients without time limits or distance restrictions, may overcome these draw-
backs (6-8).

1 2
School of Nursing,  Peking University, Beijing, China. Correspondence: Mingzi Li (limingzi2000@163.com) Department of Endocrinology,  Zhongda
Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China.
*Xue Cai and Shanhu Qiu contributed equally to this work.
© 2020 The Obesity Society. Received: 13 July 2019; Accepted: 20 October 2019; Published online 22 January 2020. doi:10.1002/oby.22715

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Obesity
As a novel technology, mobile apps have emerged as a promising tool
for diabetes self-management. Accumulating evidence has shown
that mobile app interventions can lower hemoglobin A1c (HbA1c) and
increase physical activity in patients with type 2 diabetes (7,9-11).
Yet the association between mobile app interventions and weight loss
remains inconclusive (12-15). Several randomized controlled trials
(RCTs) have reported a significant effect of mobile app interventions
on weight loss (14-17), while others argued that they had no or only
minor effects (9,10,13). Cui et al. (18) conducted a meta-analysis by
summarizing these pieces of evidence published before June 2016 in
patients with type 2 diabetes and concluded that mobile app interven-
tions may not promote weight loss (18). However, their conclusion was
merely based on data from four RCTs, which may result in an insuf-
ficient statistical power to obtain a moderate or mild but significant
result. Moreover, it remains unclear whether there exists any moderator
(e.g., the functionalities characterized by mobile apps) that may affect
the outcomes associated with mobile app interventions.
Given these factors  and considering that more RCTs on mobile app
interventions have been published since 2016, we conducted this meta-
analysis to reevaluate their effectiveness on weight loss as assessed by
body weight (BW) and other weight-related measures, including BMI
and waist circumference (WC), in patients with type 2 diabetes, along
with explorations on the sources of heterogeneity.
Methods
Data sources and search strategy
This meta-analysis was conducted following the outlines from
the Preferred Reporting Items for Systematic Reviews and Meta-
Analyses statement (Supporting Information Table S1). Although
not prospectively registered, this meta-analysis adhered to an un-
published protocol (Supporting Information Table S2). A system-
atic literature search of relevant studies on PubMed and Scopus was
performed from their inceptions to May 22, 2019, using the words
or terms related to “mobile app” and “type 2 diabetes” (Supporting
Information Table S3). In addition, grey literature, such as techni-
cal or research reports, doctoral dissertations, or conference papers,
was also searched in the database of OpenGrey. Moreover, a manual
check of the reference lists from included studies or relevant system-
atic reviews and/or meta-analyses was done to identify other suitable
studies.
Inclusion and exclusion criteria
Studies eligible for this meta-analysis had to (1) enroll participants
with type 2 diabetes aged ≥ 18 years; (2) employ interventions that used
mobile apps as the major component; (3) compare with controls that
received usual care but without mobile app interventions; (4) report
any of the following outcomes: BW, BMI, WC, fat mass, or body fat;
(5) be RCTs; and (6) get published in English. We also included stud-
ies if their mobile app intervention groups received other intervention
components identical to controls. In this study, mobile app was defined
as a software running on a mobile phone that accepts data and could
provide feedback to patients in relation to diabetes management (e.g.,
physical activity/exercise, healthy diet) (7). Studies were excluded if
they enrolled participants with type 1 diabetes, did not report outcomes
on weight loss, or were reviews or meta-analyses. Studies were also
excluded if mobile apps were simply used for communication between
patients and health care providers.
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Mobile Apps and Weight Loss in T2D  Cai et al.
Data collection and quality assessment
A self-designed data collection form was used to get the following in-
formation: study and participant characteristics (first author, publica-
tion year, study location, sample size, mean age, BW, BMI, and HbA1c
at entry, proportion of male  participants, disease duration of type 2
diabetes, intervention period, and characteristics of interventions and
controls), mobile app characteristics (functionalities and the feedback),
and outcomes (means and SDs of BW, BMI, WC, fat mass, or body fat).
If studies reported outcomes at several different time points, data from
the longest one were chosen (19).
The methodological quality of included studies was assessed using the
“Risk of Bias” tool, which includes items on selection bias, perfor-
mance bias, detection bias, attrition bias, and reporting bias (19,20). All
data collection and quality assessment were performed by two indepen-
dent investigators (XC and SQ), and kappa statistic was used to assess
the agreement between investigators (19,21). Uncertainties or discrep-
ancies were resolved by discussion with a third investigator (DL).
Data synthesis and statistical analysis
Change scores from baseline and the corresponding SDs in each RCT
were pooled to obtain the overall weight mean differences (WMDs)
and 95% CIs, using a random-effects meta-analysis model that is rec-
ognized to better account for heterogeneity (19). If change scores or
corresponding SDs were not reported, they were imputed using the
methods described previously (19,22,23). Specifically, the correlation
coefficient used to obtain the SDs of the mean changes was calculated
to be 0.93 based on the study by Anzaldo-Campos et al. (10).
Heterogeneity was assessed by I2 test, with its value  > 50% indicating
substantial heterogeneity. Subgroup and meta-regression analyses were
conducted to sort out potential sources of heterogeneity, which included
age, BMI, HbA1c, and disease duration of type 2 diabetes at baseline,
sex, study location, intervention duration, and mobile app functional-
ities. Sensitivity analyses by excluding studies having sample sizes < 50,
having dropout rates  > 20%, or employing per  protocol analyses were
performed to assess the robustness of the outcomes. Publication bias was
evaluated by funnel plot asymmetry and quantified by Begg’s test. In case
of publication bias, the trim-and-fill method was used to assess its impact
on the overall outcome (19). All the analyses were conducted using Stata
Statistical  Software (version 14.0; StataCorp, LLC, College Station,
Texas), and a two-sided P < 0.05 was considered statistically significant.
Results
Main characteristics of included studies
Of the 1,741 unique relevant studies retrieved, a total of 14 RCTs were
included in this meta-analysis upon the exclusion of 1,727 studies with
the reasons listed in Figure 1 (9-17,24-28). Specifically, one study was
excluded because it was an ad interim report (29), and another was
excluded because of inconsistent results on BW and BMI (30).
Characteristics of the 14 RCTs that enrolled 2,129 patients with type
2 diabetes are summarized in Table 1. The included patients had a
mean age of 58.4 years (51.1-66.1 years) and a mean BMI of 30.0
kg/m2 (23.5-38.1). The duration of mobile app interventions varied
from 3 to 12 months. Most studies were conducted in American or
European countries (9-14,17,26,27) and only five in Asian countries
(15,16,24,25,28).
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Original Article
CLINICAL TRIALS AND INVESTIGATIONS
Figure 1 Study selection process.
Details of the mobile app interventions are shown in Supporting
Information Tables S4 and S5. All mobile apps were designed to improve
diabetes self-management by providing feedback tailored to automatically
transferred or manually entered information on exercise, diet, weight, or
blood glucose. Only one mobile app included the function of calculat-
ing insulin bolus using an insulin dose adjustment algorithm based on
glucose levels (15). Of the 14 RCTs, 11 applied intention-to-treat anal-
ysis (Supporting Information Table S6). Almost all studies had dropout
rates < 20% except one by Holmen et al. (13). The overall kappa value was
0.87 (P < 0.001) for agreement on data collection, and 0.82 (P < 0.001) on
study quality assessment between investigators (XC and SQ).
Effect of mobile app interventions on BW
Nine RCTs with 785 patients reported outcomes on BW, with two
showing significant results favoring mobile app interventions (17,27).
Pooled results suggested that mobile app interventions were associated
with a reduction in BW by 0.84 kg (95% CI: 1.51 to 0.17 kg; Figure 2A),
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Obesity
along with some evidence of moderate heterogeneity (I2 = 49%).
Subgroup analysis observed a higher reduction in BW associated with
mobile app interventions in patients with obesity (BMI > 30) than in
those who were lean or had overweight (BMI ≤ 30) (P = 0.001; Table 2).
Meta-regression analysis using BMI as a continuous variable showed
that mobile app interventions resulted in a BW reduction of 0.15 kg for
every 1-kg/m2 increase in baseline BMI (P = 0.01; Figure 2B).
Mobile app interventions led to a weaker BW reduction in Asians than
non-Asians (mainly Americans or Europeans) (P = 0.001). However,
when mobile app interventions were combined with additional behavior
interventions, such as multidisciplinary diabetes care management or
health coaching, they seemed to yield a larger BMI reduction than using
mobile app interventions alone (P = 0.08; Table 2). The functionalities
associated with mobile apps (e.g., physical activity, diet, weight, or
glucose recording/monitoring) may not influence the outcome on BW
reduction (all P > 0.50). Moreover, age, glycemic control (assessed by
HbA1c), and intervention duration were also not significant moderators
Obesity | VOLUME 00 | NUMBER 00 | MONTH 2020     
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Obesity Mobile Apps and Weight Loss in T2D  Cai et al.

TABLE 1 Baseline characteristics of included studies

Study Male Age BMI BW HbA1c T2D Study Outcome

First author, year location (%) (y) (kg/m2) (kg) (%) duration (y) duration (mo) measures
Alonso-Domínguez, 2019 Spain 54.4 60.6 29.9 NA 6.9 NA 12 BMI, WC
Anzaldo-Campos, 2016 Mexico 30.8 51.1 30.9 NA 11.3 8.3 10 BMI
Bender, 2017 US 38 57.6 30.1 75.8 7.4 NA 3 BW, BMI, WC
Faridi, 2008 US 36.7 56 35.6 97.1 6.5 NA 3 BW, BMI
Holmen, 2014 Norway 63.4 57.3 32.2 97 8.2 10.3 12 BW
Karhula, 2015 Finland 54.4 66.1 31 89.3 7.2 > 0.25 12 BW, WC
Kim, 2019 Korea 51.7 58.4 25.7 68.1 7.8 12.9 6 BW
Kumar, 2018 India 34.9 57.3 24.4 NA NA NA 12 BMI
Orsama, 2013 Finland 54 61.9 32.1 NA 7.0 11.7 10 BW
Sun, 2019 China 40.7 68 23.5 NA 7.9 11.4 6 BMI
Waki, 2014 Japan 75.9 57.3 26.7 NA 7.1 9.1 3 BMI
Wang, 2018 US 41.2 54 36.3 98.7 8.7 12.2 6 BW
Wayne, 2015 Canada 28 53.2 35.4 96.2 8.8 NA 6 BW, BMI, WC
Yoo, 2009 Korea 58.6 58.2 25.6 67.1 7.5 6.6 3 BW, BMI, WC

BW, body weight; HbA1c, hemoglobin A1c; NA, not applicable; T2D, type 2 diabetes; WC, waist circumference.

Figure 2 Effect of mobile application interventions on body weight in patients with type 2 diabetes. (A) Meta-analysis of mobile application interventions on body weight.
(B) Meta-regression analysis on body weight based on BMI.

of the reduction in BW  resulting from mobile app interventions (all
P > 0.05; Supporting Information Table S7). Sensitivity analyses by
excluding studies having dropout rates > 20%, having sample sizes < 40,
or employing per  protocol analyses did not alter the overall outcome
substantially. The funnel plot seemed to be asymmetrical (Supporting
Information Figure S1A), but the Begg’s test suggested no evidence of
significant publication bias (P = 0.47). Further analysis using the trim-
and-fill method did not identify any missing study, leaving the primary
outcome unchanged (WMD −0.84 kg, 95% CI: −1.51 to −0.17 kg).
Effect of mobile app interventions on other
weight-related measures
BMI.  Nine RCTs enrolling 1,605 patients were included. Results from
the meta-analysis suggested that mobile app interventions had a trivial
but nonsignificant effect in reducing BMI (−0.08, 95% CI: −0.41 to
0.25), with evidence of substantial heterogeneity (I2 = 64%; Figure 3A).
Subgroup analyses did not detect any significant moderator, but it is likely
that the reduction in BMI was larger in patients with obesity or in studies
using mobile app interventions jointly with other behavior interventions
(Table 2). Meta-regression analysis indicated that age might affect the
changes in BMI that resulted from mobile app interventions (P = 0.03;
Supporting Information Table S7). Sensitivity analyses upon the removal
of studies with dropout rates > 20%, sample sizes < 40, or per protocol
analyses did not change the results remarkably. The funnel plot was
symmetrically shaped (Supporting Information Figure S1B), and no
evidence of publication bias was detected by Begg’s test (P = 0.60).
WC.  Five RCTs with 618 patients were eligible for this meta-analysis.
Results showed that mobile app interventions decreased WC by 1.35 cm
(95% CI: 2.16 to 0.55 cm; I2 = 8%; Figure 3B). Subgroup analyses showed
that a more pronounced decrease in WC was observed in patients with

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 Original Article

www.obesityjournal.org 
TABLE 2 Subgroup analyses

BW BMI WC

No. WMD (95% CI) (kg) I2 No. WMD (95% CI) (kg/m2) I2 No. WMD (95% CI) (cm) I2
CLINICAL TRIALS AND INVESTIGATIONS

BMI
> 30 kg/m2 7 −1.30 (−1.96 to −0.63) < 1% 4 −0.35 (−0.76 to 0.06) < 1% 3 −2.06 (−3.12 to −1.00) < 1%
≤ 30 kg/m2 2 −0.20 (−0.29 to −0.11) < 1% 5 0.08 (−0.36 to 0.51) 77% 2 −0.56 (−1.65 to 0.52) < 1%
Country
Asian 2 −0.20 (−0.29 to −0.11) < 1% 4 0.07 (−0.56 to 0.70) 82% 1 −0.50 (−1.72 to 0.72) NA
Non-Asian 7 −1.30 (−1.96 to −0.63) < 1% 5 −0.16 (−0.51 to 0.20) 27% 4 −1.85 (−2.82 to −0.88) < 1%
Control group
Usual care 7 −0.54 (−1.15 to 0.07) 32% 6 0.05 (−0.39 to 0.48) 74% 3 −1.01 (−1.87 to −0.16) < 1%
Others 2 −1.70 (−2.81 to −0.58) < 1% 3 −0.33 (−0.75 to 0.08) < 1% 2 −2.53 (−4.20 to −0.86) < 1%
Exercise recording/monitoring
With 8 −0.95 (−1.77 to −0.14) 54% 9 −0.08 (−0.41 to 0.25) 64% 4 −1.28 (−2.38 to −0.19) 22%
Without 1 −0.60 (−1.76 to 0.56) NA NA NA NA 1 −1.74 (−3.11 to −0.37) NA
Diet recording/monitoring
With 6 −0.93 (−1.85 to −0.02) 50% 8 −0.10 (−0.49 to 0.29) 68% 3 −1.96 (−3.33 to −0.59) < 1%
Without 3 −0.82 (−2.13 to 0.50) 53% 1 0.00 (−0.47 to 0.47) NA 2 −1.08 (−2.29 to 0.13) 43%
Weight recording/monitoring
With 5 −1.04 (−2.14 to 0.07) 32% 6 −0.15 (−0.40 to 0.10) 31% 4 −1.25 (−2.14 to −0.35) 15%
Without 4 −0.76 (−1.70 to 0.18) 59% 3 0.04 (−1.20 to 1.27) 82% 1 −2.35 (−4.72 to 0.02) NA
Glucose recording/monitoring
With 7 −0.76 (−1.48 to −0.03) 55% 6 −0.03 (−0.46 to 0.41) 72% 3 −1.28 (−2.32 to −0.24) 28%
Without 2 −1.59 (−3.38 to 0.21) < 1% 3 −0.31 (−1.15 to 0.53) 51% 2 −1.77 (−3.63 to 0.09) 19%

BW, body weight; NA not applicable; WC, waist circumference; WMD, weighted mean difference.
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Figure 3  Effects of mobile application interventions on BMI and waist circumference in patients with type 2 diabetes. (A) Meta-analysis of mobile application
interventions on BMI. (B) Meta-analysis of mobile application interventions on waist circumference.
obesity or in studies using mobile app interventions combined with
other behavior interventions (Table 2). The shape of the funnel plot was
symmetrical (Supporting Informamtion Figure S1C), and no evidence of
significant publication bias was observed (P = 0.81 for Begg’s test).
Other measures.  There was only one study investigating the effects
of mobile app interventions on fat mass and percentage of body fat,
which were measured using bioelectrical impedance analysis (15).
This study showed that mobile app interventions decreased fat mass by
0.4 kg and lowered the percentage of body fat by 0.6% (15).
Discussion
Main findings
This meta-analysis, which incorporated data from 14 RCTs enrolling
more than 2,100 patients with type 2 diabetes, indicated that mobile
6     Obesity | VOLUME 00 | NUMBER 00 | MONTH 2020
Mobile Apps and Weight Loss in T2D  Cai et al.
app interventions were associated with significant reductions in BW by
0.84 kg and WC by 1.40 cm but merely with a nonsignificant decrease in
BMI by 0.08. These reductions were larger among patients with obesity
(as indicated by BMI > 30) and in studies using mobile app interventions
combined with other behavior components. However, weight loss was not
significantly moderated by the functionalities of the mobile apps (e.g.,
exercise/physical activity, diet, weight, or glucose recording/monitoring).
Interpretations and implications
Our meta-analysis suggested that mobile app interventions were
effective in reducing BW. Yet this finding contrasts with the result
from a prior study that mobile app interventions were not able to sig-
nificantly reduce BW in patients with type 2 diabetes (18). It seems
likely that the small sample size in the latter study might be largely
responsible for this inconsistency. Notably, apart from the reduction
in BW, our meta-analysis provided further evidence that mobile app
interventions could lower WC and decrease fat mass as well as the
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CLINICAL TRIALS AND INVESTIGATIONS
percentage of body fat. These findings indicate that mobile apps, one
type of mobile health intervention, might be an effective approach
for obesity management (31-33). However, we did not find a sig-
nificant reduction in BMI from mobile app interventions in patients
with type 2 diabetes. This might be due to the evidence that BW and
WC are more direct and sensitive measures to reflect weight change
compared with BMI.
Yet it should be mentioned that the reductions in BW and WC were very
mild in patients with type 2 diabetes (less than 2.5% of the corresponding
baseline BW and WC). However, such tiny changes might be already of
significant clinical importance because in 2016, Zomer et al. (2) demon-
strated that a weight loss of less than 2.5% was correlated with improved
glycemic control, lowered blood pressure, and altered lipid profiles.
Furthermore, the reduction in BW related to mobile app interventions was
comparable to that from pedometer interventions, which are specifically
designed to promote unstructured physical activity (34).
Our findings have several potential implications for clinical practice.
First, as noted by our subgroup and meta-regression analyses, mobile app
interventions might be more suitable for patients with obesity in terms of
promoting weight loss. Because these patients are vulnerable to weight
regain after successful weight loss (35), it might be of interest to assess
whether mobile app interventions would be helpful to maintain weight
loss and prevent weight regain. Moreover, the low dropout rates (< 20%)
reported in almost all included RCTs would make the mobile app inter-
ventions attractive and attainable for a time-poor population with type 2
diabetes. Second, larger reductions in BW, BMI, and WC were observed
among studies comparing mobile app interventions plus additional behav-
ior components with identical behavior components than those compar-
ing mobile app interventions with usual care alone. This implies that
the effectiveness of mobile app interventions on weight loss could be
augmented by incorporating additional behavior components, including
multidisciplinary diabetes care management or health coaching (10,27).
Third, our study showed that none of the single functionalities designed
on the mobile apps, such as to record or monitor physical activity, diet,
weight, or glucose, could yield a significant impact on weight loss. This
might be because all studied mobile apps had four to five functionalities
on average, and it is therefore difficult to distinguish between individual
effects. Finally, even though better compliance was observed in the short-
term mobile app interventions compared with the long-term ones (9,10),
our meta-analysis did not provide strong evidence that the intervention
period would substantially affect the outcomes on weight loss.
Strengths and limitations
Our meta-analysis is, to date, the most comprehensive study that has
explored the benefit of mobile app interventions on weight loss as re-
flected by several weight-related health measures in patients with type 2
diabetes. Moreover, the inclusion of only RCTs might help to minimize
the risk of bias or confounding on observed outcomes. Notably, our
study provided evidence in support of the strengths of meta-analyses
in identifying meaningful while small changes by enhanced statistical
power (23), as only less than 5 individual studies of the included 14
RCTs reported significant outcomes on weight loss.
However, our meta-analysis has several limitations. First, although the
definition of mobile app in our study referred to the one described by
Hou et al.  (7), there is still a lack of a clear definition to date (36).
Second, changes in weight-related health measures in almost all
included RCTs were not reported as the primary outcomes, which may
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Obesity
underpower the influence of mobile app interventions on weight loss.
Third, because of the nature of behavioral interventions for mobile
apps, the blinding of participants and personnel is impossible. Yet
this appears unlikely to affect the outcomes we chose, as they were
all objectively measured. Finally, although there was some evidence of
publication bias detected by funnel plot for the result on BW, the trim-
and-fill method suggested that such a bias may not significantly affect
the primary analysis. Moreover, the inclusion of only RCTs published
in English may still incur selection or publication bias.
Conclusion
Mobile app interventions could promote weight loss, especially in
patients with type 2 diabetes and obesity, albeit at a mild magnitude.
Future studies would benefit from employing additional behavior com-
ponents jointly with mobile app interventions to obtain larger weight
loss. Moreover, to enable full use of mobile app interventions, it might
be worth examining whether they would help to sustain weight loss or
prevent weight regain in patients with type 2 diabetes and obesity who
had received successful weight loss interventions. O
Disclosure: The authors declared no conflict of interest.
Author contributions: XC designed the study, collected and analyzed the data, and
wrote the manuscript. SQ collected and analyzed the data and contributed to the
discussion. DL, LW, and YL contributed to the discussion and edited the manuscript.
ML designed the study, contributed to the introduction, and reviewed/edited the
manuscript. All authors read and approved the final manuscript.
Supporting information: Additional Supporting Information may be found in the
online version of this article.
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