Individual Patient Data Meta-Analysis for

observational research – a case study of mobile

phone use and mental health in India

MRC Journal Club

28th May 2021
Alex Spiers
Supervised by Mireille B. Toledano, Faisal Ahmed and Martina di Simplicio
Hello from me
MRC Journal Club – the brief?
My Research: Mobile Phone Usage and Mental Health in
cVEDA Cohort
Aim: Determine effects mobile technology usage in LMIC-setting on
• behavioural problems
• internalizing disorders (anxiety and depression)
Background
Increase in smartphone ownership and use of social
media use hypothesized as major causes in a recent
secular trend of increasing:
– internalizing symptoms
– poorer well-being
– self-harm/suicidal behaviours in adolescent
Active mobile-broadband subscriptions per 100
populations – Twenge et al. (2018) inhabitants

ITU - Facts and figures (2020)

Evidence not clear – and very sparse in LMIC -
although there are some exceptions, e.g.
Mortazavi et al. (2011)
Mobile Phone Use and Mental Health - mechanisms

Displacement of healthy Emotionally salient and Positive peer relationships

activities e.g. sleep / harmful content and/or negative peer
physical activity interactions
The CVEDA Cohort
• Established to investigate the vulnerabilities for
development of mental health problems
• Represents the socio-cultural diversity of India
• Seven recruitment catchments in six geographical
regions
• Urban, rural & slum areas
• Familial and environmental high-risk sub-
populations
 Adolescents & young adults
Aged 13-22
Methods N = 5728

Exposure Outcomes Covariates

Self-reported daily duration Strengths and difficulties Age

of mobile phone use in questionnaire (SDQ)
these categories: continuous Sex

Calls Anxiety (GAD/SAD) SES (housing quality,

1 or 0 homeownership)
Instant Messaging
Depression (MDD) Neighbourhood
Social Media 1 or 0 classification (urban, slum,
rural)
Recruitment in CVEDA
• Non-probabilistic convenience sampling based on accessibility to potential
participants in local schools, colleges, community and clinics
• Unclear proportion of clinical and community samples
• Sample cannot generalise to whole population of India

• Q. What would you need in order to have a representative sample of

253 million adolescents?
Heterogeneity between recruitment sites
Why might there be heterogeneity in mobile phone effects?
“Online risks mirror offline vulnerabilities”
• Adolescents with a history of prior victimization are more likely to be bullied, victimized,
and solicited online (Kowalski, Giumetti, Schroeder, & Lattanner, 2014)

• Adolescents with mental health problems more likely to seek out more negative online
content and spend more time passively ‘lurking’ versus engaging with others
(Underwood & Ehrenreich, 2017).

• Some Bengaluru and Rishi Valley participants have impaired cognition from arsenic
exposure (Vaidya et al., in press)
IPD random effects meta-analysis of epidemiological
data
• Main aim of IPD meta-analysis is to quantify exposure-disease
associations using individual-level data from relevant population samples

• Usually conducted as part of systematic review

• Participant level data also allows more comprehensive and appropriate

analyses e.g.
– time-to-event / survival
– subgroup analyses.
Why use IPD meta-analysis methods?
estimate mean
integrate quantify
effects and
multiple study- heterogeneity of
site/study
designs findings
effects

predict of effect
in a new study, hypothesis
testing
θnew
So you want to use IPD meta-analysis methods? What
now?
Classical Estimation of IPD-MA
• Two stage: create summary statistics out of IPD (stage 1) and combine using
standard meta-analysis method (stage 2)
– e.g. Dersimonian-Laird
• One stage: combine all patient data from all studies in one single
(hierarchical) model taking into account the clustering of patients within
study
Two-stage DL Random Effects IPD-MA
1. Fit model and evaluate exposure effect for each study/site
2. Assume:


3. Obtain meta-analysis results using inverse variance approach:

a) b) c)
 Pros & cons of two-stage IPD-MA
Advantages of two-stage IPD MA:
• Straightforward fitting of models
• Allows within-study inferences
• Forest-plots easy to interpret and view
heterogeneity
• Within-study/site clustering accounted
for
• Different exposure effects estimated
for each site
Disadvantages of two-stage IPD MA:
• Relies on Central Limit Theorem –
issue with rare outcomes or few
studies (i.e. asymptotic normality)
• Separation issue for binary
response
• estimation methods for τ2 may fail to
converge resulting in
anticonservative CI intervals
• Cannot use information from other
studies e.g. for missing data models
 One-stage IPD meta-analysis
• combine all patient data from all studies in one single (hierarchical) model
• Continuous outcomes assuming random effects for effect
– For participant in study/site

𝑦 𝑖𝑗=𝛼 𝑗 + 𝛽 𝑗 𝑥𝑖𝑗 + 𝜀𝑖𝑗

𝜀𝑖𝑗 𝑁 0,𝜎 )
( 2
Extension to adjustment factors

• For participant in study/site

• Exposure
• Adjustment factors
from 1, … , k
Pros & cons of one-stage IPD-MA
Advantages of one-stage IPD MA: Disadvantage of one-stage IPD MA:
• most flexible approach • A small number studies still brings
• more reliable results than the two- into question the use of ML-based
stage method when few studies or inference.
few subjects per study are available • convergence issues
• can model correlation of adjustment
factors
Issues with classical / frequentist IPD-MA estimation
• Estimation methods for τ2 often fail to converge because of small numbers of
studies in the meta-analysis or large within-study variances (τ2 often
estimated to be zero - Chung et al., 2013)
• Type I error rates and coverage probabilities for meta-analytic estimates are
not necessarily at expected levels especially if:
– Few studies
– Small numbers of participants
– Binary response, particularly rare events
Bayesian Framework for one-stage IPD Meta-Analysis
• Data and model parameters are considered to be random quantities
• Exact inference with MCMC - All parameter uncertainty (including for τ2) is
automatically accounted for in the analysis.
• Posterior distributions for parameters of interest allow probability
statements to be made directly regarding quantities of interest
• Studies in meta-analysis can “borrow strength” from other studies
• Now easier than ever to implement in STAN using HMC
Bayesian Framework for one-stage IPD Meta-Analysis
• Requires prior distributions for parameters
– All model coefficients
– All variance components
• Thinking about even weakly informative priors is challenging – steep learning
curve, many false starts!
Comparing two-stage, & Bayesian one-stage IPD-MA
Modelling association between SDQ Total difficulties & Call duration
• )
•
 Two-stage
Two-stage DL RE IPD-MA
DL random-effects

Effect of call duration on SDQ Score

Bayesian one-stage IPD-MA

Comparing two-stage, & Bayesian one-stage IPD-MA
Modelling Social media and Anxiety Disorder association
• Anxiety disorderi ~Bernoulli()
•

• Anxiety disorder is rare (1%)

• Some sites have very low internet phone use i.e. very few
participants with any exposure
 Two-stage DL RE IPD-MA

Social Media Duration on Depression OR

Bayesian one-stage IPD-MA

Conclusions
• IPD-meta-analysis (or –like methods) are useful for epidemiological research,
especially for:
– Evidence synthesis from multiple studies
– Exploring heterogeneity
• Different assumptions can change single-study inferences, but pooled effects
are generally robust to choice of estimation
 Thanks for listening!

Acknowledgements
Dr Gwen Fernandes
Dr Jon Heron
Nilakshi Vaidya
 Mobile Phone Ownership – Recruitment Centre

IMPHAL KOLKATA MYSORE NIMHANS PGIMER RISHIVALLEY

(N=802) (N=664) (N=1339) (N=1522) (N=862) (N=318) SJRI (N=613) Total (N=6120)
Currently own
mobile phone?
never used 0 (0.0%) 272 (49.4%) 129 (9.7%) 57 (3.8%) 47 (6.7%) 2 (0.6%) 210 (37.2%) 717 (12.5%)
never owned 315 166 (30.1%) 270 (20.3%) 692 (46.7%) 259 (37.2%) 240 (76.4%) 323 (57.2%) 2265 (39.5%)
(39.5%)
used to own 43 (5.4%) 5 (0.9%) 91 (6.9%) 31 (2.1%) 23 (3.3%) 2 (0.6%) 1 (0.2%) 196 (3.4%)
currently own 440 108 (19.6%) 837 (63.1%) 701 (47.3%) 368 (52.8%) 70 (22.3%) 31 (5.5%) 2555 (44.6%)
(55.1%)
missing 4 113 12 41 165 4 48 387
Use phone to
connect to
internet?
do not own 358 443 (80.4%) 490 (37.0%) 780 (52.7%) 329 (47.3%) 244 (77.7%) 534 (95.0%) 3178 (55.5%)
(44.9%)
No 21 (2.6%) 25 (4.5%) 125 (9.4%) 79 (5.3%) 34 (4.9%) 8 (2.5%) 12 (2.1%) 304 (5.3%)
Yes 419 83 (15.1%) 711 (53.6%) 621 (42.0%) 333 (47.8%) 62 (19.7%) 16 (2.8%) 2245 (39.2%)
(52.5%)