Rotavirus burden among children under-5: Results from the Global Burden of Disease Study 2017

Christopher Troeger, August 2018ctroeger@uw.eduInstitute for Health Metrics and Evaluation

GBD Overview

• A systematic, scientific effort to quantify the comparative magnitude of health loss from all major diseases, injuries, and risk factors

• Comprehensively and comparablyproduces annual estimates at the global, regional, and country levels by sex and age group for:

1. Cause-specific mortality

2. Disability-adjusted life years (DALYs) due to specific diseases, injuries, and risk factors

GBD OverviewEngaging an international research collaboration

• Over 1,300 GBD collaborators in 114 countries contribute to analysis of data, provide country-specific insights, and champion the use of data for policymaking.

• Join our endeavor (especially if you are from any country not colored in green)!

GBD OverviewEngaging an international research collaboration

• Over 1,300 GBD collaborators in 114 countries contribute to analysis of data, provide country-specific insights, and champion the use of data for policymaking.

• Join our endeavor (especially if you are from Belarus)!

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GBD OverviewProducing multiple metrics for health

• GBD 2016 adheres to the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER)

• Each step of the estimation process is documented and available including input data

• Visualization tools are publicly available at http://www.healthdata.org/results/data-visualizations

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GBD OverviewProducing multiple metrics for health

• GBD 2016 adheres to the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER)

• Each step of the estimation process is documented and available including input data

• Visualization tools are publicly available at http://www.healthdata.org/results/data-visualizations

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Rotavirus in GBD

https://jamanetwork.com/journals/jamapediatrics/fullarticle/2696431

Highlights from GBD

• Diarrhea is the third leading infectious cause of under-5 mortality globally, responsible for 533,800 deaths in 2017

• Still, there has been major progress in reducing under-5 diarrhea mortality. The diarrhea mortality rate in this age group decreased by 70% since 1990 and by 44% since 2007

• Rotavirus is the leading cause of diarrhea mortality among children under-5 and for all ages

• Diarrhea mortality is largely preventable and is highly influenced by poor water, sanitation, and hygiene infrastructure, childhood undernutrition, and by the existing rotavirus vaccines

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Methods

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To overcome the challenges in diarrhea burden estimation, we model burden using three distinct pathways

Diarrhea mortality estimatesModeling Platform: Cause of Death Ensemble model framework (CODEm)• Sources of data: vital

registration systems, verbal autopsy, and surveillance systems

• Sparse data in high-burden geographic regions

• Maximizes predictive validity for areas without data

Diarrhea morbidity estimatesModeling Platform: DisMod-MR meta-regression tool• Sources of data: surveys,

scientific literature, hospitalization records

• Ensures comparability of these data

• Relates incidence, prevalence, recovery, and mortality

Etiology estimates• Calculate a population

attributable fraction to estimate episodes and deaths due to 13 enteric pathogens

• Attribution based on a molecular diagnostic (PCR) case definition

• Adjust all diagnostic data to be consistent with molecular diagnostic definition

Global Burden of Diarrhea

• Overall diarrhea mortality and morbidity is estimated separately from the etiologies

• Mortality is estimated using an ensemble modeling platform (CODEm)

• Incidence and prevalence are estimated using a meta-regression modeling tool (DisMod)

• Produces estimates of diarrhea and etiology-specific burden by age, sex, location, and time

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• Bayesian, mixed-effects regression model (Cause of Death Ensemble model [CODEm])o Vital registration, verbal autopsy, surveillance

o Suite of independent sub-models

• Estimates by age, sex, year, geography

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Females, Peru

http://vizhub.healthdata.org/cod/

Fatal modeling: key points

Females, Pakistan

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Mortality modeling details

• Diarrhea summary exposure variable (SEV)

• Stunting, wasting, underweight prevalence

• Unsafe water and sanitation• Handwashing• Rotavirus vaccine coverage• Breastfeeding• Vitamin A and zinc deficiency• Healthcare access and quality• Income per capita• Maternal education• Socio-demographic status• Population densityCountry-years of data used in model

Covariates used in model

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• Case definition: o 3 or more loose stools in 24 hour period

• Incidence, prevalence, remission excess mortality modeled simultaneouslyo Age-integrating meta-regression toolo Compartmental model of disease

• Uses Socio-demographic Index, Healthcare access and quality index, and unsafe water and sanitation as covariates

Non-fatal modeling: key points

Data sources used in non-fatal modeling

• Input data include• Hospital admissions and visits,• Population representative surveys• Cross-sectional and cohort data from scientific literature

Diarrhea etiology estimation: key points

• Population attributable fractions (PAFs) are a counter-factual approach to etiologic attribution

𝑃𝑃𝑃𝑃𝑃𝑃 = 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 ∗ 1 −1𝑂𝑂𝑂𝑂

• These PAFs are produced for each sex, age, year, and geographyo Molecular diagnostic reference definition

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Proportion of diarrhea episodes

𝑃𝑃𝑃𝑃𝑃𝑃 = 𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷 ∗ 1 −1𝑂𝑂𝑂𝑂

• Systematic literature review from 1990-2017 for the proportion of diarrhea episodes that test positive for each pathogen

• Adjust values based on sensitivity/specificity of traditional diagnostics to molecular diagnostic reference definition

• Meta-regression (DisMod) to produce produce age, location, sex, time specific estimates for the proportion of diarrhea episodes positive for each pathogen

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Rotavirus proportion data sources (n = 524)

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Sensitivity of ELISA to molecular diagnostic

Under-detect rotavirus by 13-27%

Odds ratios

𝑃𝑃𝑃𝑃𝑃𝑃 = 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 ∗ 1 −1𝑶𝑶𝑶𝑶

• By age group, estimate the odds of diarrhea given the presence of each pathogen

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Odds Ratios𝑃𝑃𝑃𝑃𝑃𝑃 = 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 ∗ (1 −

1𝑶𝑶𝑶𝑶)

• By age group, estimate the odds of diarrhea given molecular detection of each etiology

• Mixed-effects generalized additive model regression accounting for pathogen interactions and case-control matching

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Odds Ratios

Odds RatiosUnder 1 Over 1

Fatal 12.4 (9.2-16.2) 13.7 (8.7-20.9)Non-fatal 8.2 (6.1-10.9) 7.0 (4.7-9.9)

Results

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Etiologic attribution for rotavirus in 2017

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Age Deaths Mortality rate Attributable Fraction

Under 5 185,390 (145,565-224,346) 27.2 (21.4-33.0) 34.7% (29.2-40.4%)

All ages 329,360 (259,772-424,023) 4.3 (3.4-5.6) 21.1% (17.7-24.8%)

Etiologic attribution for rotavirus in 2017

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Age Deaths Mortality rate Attributable Fraction

Under 5 185,390 (145,565-224,346) 27.2 (21.4-33.0) 34.7% (29.2-40.4%)

All ages 329,360 (259,772-424,023) 4.3 (3.4-5.6) 21.1% (17.7-24.8%)

Etiologic attribution for rotavirus in 2017

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Age Deaths Mortality rate Attributable Fraction

Under 5 185,390 (145,565-224,346) 27.2 (21.4-33.0) 34.7% (29.2-40.4%)

All ages 329,360 (259,772-424,023) 4.3 (3.4-5.6) 21.1% (17.7-24.8%)

Rotavirus mortality rate in 1990

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Rotavirus mortality rate in 2017

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Central African Republic (310/100,000)

Rotavirus attributable fraction in 2017

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Rotavirus deaths in 2017

Nigeria (55,000)

Burden by super region

Deaths Mortality rate per 100,000150,000

100,000

50,00025

50

75

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Rotavirus vaccine

• Modeled using surveys and implementation program datao Estimated as ratio of rotavirus vaccine coverage to DTP3

coverage

• Low vaccine coverage considered a risk factoro Estimated as counterfactual compared to full coverageo Vaccine efficacy from Lamberti et al 2016

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Rotavirus vaccine coverage

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2010: 9.2%

2015: 31.4%

2017: 50.0%

Impact of rotavirus vaccine

• Estimated that in 2016, rotavirus vaccine averted 28,000 deaths among children under-5 (14,600-46,700)

• This represented 15.3% of potentially avertable deaths

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Impact of rotavirus vaccine

• Full use of the vaccine could have prevented 83,200 deaths in 2016 (37,000 – 168,000)

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Impact of rotavirus vaccine

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Comparisons with other estimates

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Comparison between GBD iterations: etiologies

Comparison with other groups

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183392

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Comparison with other groups

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• At least two other groups estimate global under-5 deaths due to rotavirus

Group Deaths Proportion

GBD 2017 (2017) 185,390 35%

CHERG/MCEE (2013)1 157,398 27%

WHO/CDC (2013)2 215,757 37%

1. Lanata et al 2013. Global causes of diarrheal disease mortality in children <5 years of age: a systematic review; https://www.ncbi.nlm.nih.gov/pubmed/24023773/

2. Tate et al 2016. Global, Regional, and National Estimates of Rotavirus Mortality in Children <5 Years of Age, 2000-2013; https://www.ncbi.nlm.nih.gov/pubmed/27059362

Ongoing work

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Geospatial models of diarrhea prevalence, incidence, and mortality among children under-5

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Visualization tools

• GBD Compare: https://vizhub.healthdata.org/gbd-compare• EpiViz (non-fatal modeling): https://vizhub.healthdata.org/epi/• CodViz (fatal modeling): https://vizhub.healthdata.org/cod/• Input data: https://ghdx.healthdata.org

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Conclusions

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Conclusions

• Rotavirus is the leading cause of under-5 diarrhea mortality• Rotavirus diarrhea is ubiquitous and affects children globally• The rotavirus vaccine has prevented tens of thousands of

deaths and full use could prevent many more• Global Burden of Disease study seeks to provide timely and

comprehensive estimates of diarrhea and rotavirus morbidity and mortality

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Thank you!Brigette Blacker, Bobby Reiner, Chris Troeger, and Ibrahim Khalil

on behalf of the IHME stool squad!

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