Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study: a reanalysis of the GEMS case-control study

Jie Liu; James A. Platts-Mills; Jane Juma; Furqan Kabir; Joseph Nkeze; Catherine Okoi; Darwin J. Operario; Jashim Uddin; Shahnawaz Ahmed; Pedro L. Alonso; Martin Antonio; Stephen M. Becker; William C. Blackwelder; Robert F. Breiman; Abu S.G. Faruque; Barry Fields; Jean Gratz; Rashidul Haque; Anowar Hossain; M. Jahangir Hossain; Sheikh Jarju; Farah Qamar; Najeeha Talat Iqbal; Brenda Kwambana; Inacio Mandomando; Timothy L. McMurry; Caroline Ochieng; John B. Ochieng; Melvin Ochieng; Clayton Onyango; Sandra Panchalingam; Adil Kalam; Fatima Aziz; Shahida Qureshi; Thandavarayan Ramamurthy; James H. Roberts; Debasish Saha; Samba O. Sow; Suzanne E. Stroup; Dipika Sur; Boubou Tamboura; Mami Taniuchi; Sharon M. Tennant; Deanna Toema; Yukun Wu; Anita Zaidi; James P. Nataro; Karen L. Kotloff; Myron M. Levine; Eric R. Houpt

doi:10.1016/s0140-6736(16)31529-x

Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study: a reanalysis of the GEMS case-control study

Jie Liu, James A. Platts-Mills, Jane Juma, Furqan Kabir, Joseph Nkeze, Catherine Okoi, Darwin J. Operario, Jashim Uddin, Shahnawaz Ahmed, Pedro L. Alonso, Martin Antonio, Stephen M. Becker, William C. Blackwelder, Robert F. Breiman, Abu S.G. Faruque, Barry Fields, Jean Gratz, Rashidul Haque, Anowar Hossain, M. Jahangir HossainSheikh Jarju, Farah Qamar, Najeeha Talat Iqbal, Brenda Kwambana, Inacio Mandomando, Timothy L. McMurry, Caroline Ochieng, John B. Ochieng, Melvin Ochieng, Clayton Onyango, Sandra Panchalingam, Adil Kalam, Fatima Aziz, Shahida Qureshi, Thandavarayan Ramamurthy, James H. Roberts, Debasish Saha, Samba O. Sow, Suzanne E. Stroup, Dipika Sur, Boubou Tamboura, Mami Taniuchi, Sharon M. Tennant, Deanna Toema, Yukun Wu, Anita Zaidi, James P. Nataro, Karen L. Kotloff, Myron M. Levine, Eric R. Houpt

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Abstract

Background Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). Methods GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. Findings We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2–96·0) at the population level, compared with 51·5% (48·0–55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6–80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. Interpretation A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. Funding Bill & Melinda Gates Foundation.

Original language	English
Pages (from-to)	1291-1301
Number of pages	11
Journal	The Lancet
Volume	388
Issue number	10051
DOIs	https://doi.org/10.1016/s0140-6736(16)31529-x
Publication status	Published - 24 Sept 2016
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/s0140-6736(16)31529-x

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Liu, J., Platts-Mills, J. A., Juma, J., Kabir, F., Nkeze, J., Okoi, C., Operario, D. J., Uddin, J., Ahmed, S., Alonso, P. L., Antonio, M., Becker, S. M., Blackwelder, W. C., Breiman, R. F., Faruque, A. S. G., Fields, B., Gratz, J., Haque, R., Hossain, A., ... Houpt, E. R. (2016). Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study: a reanalysis of the GEMS case-control study. The Lancet, 388(10051), 1291-1301. https://doi.org/10.1016/s0140-6736(16)31529-x

@article{95bc6d571f104f509344fd74ab6187c8,

title = "Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study: a reanalysis of the GEMS case-control study",

abstract = "Background Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). Methods GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. Findings We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3\% (95\% CI 83·2–96·0) at the population level, compared with 51·5\% (48·0–55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8\% (74·6–80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5\%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9\%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. Interpretation A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. Funding Bill \& Melinda Gates Foundation.",

author = "Jie Liu and Platts-Mills, \{James A.\} and Jane Juma and Furqan Kabir and Joseph Nkeze and Catherine Okoi and Operario, \{Darwin J.\} and Jashim Uddin and Shahnawaz Ahmed and Alonso, \{Pedro L.\} and Martin Antonio and Becker, \{Stephen M.\} and Blackwelder, \{William C.\} and Breiman, \{Robert F.\} and Faruque, \{Abu S.G.\} and Barry Fields and Jean Gratz and Rashidul Haque and Anowar Hossain and Hossain, \{M. Jahangir\} and Sheikh Jarju and Farah Qamar and Iqbal, \{Najeeha Talat\} and Brenda Kwambana and Inacio Mandomando and McMurry, \{Timothy L.\} and Caroline Ochieng and Ochieng, \{John B.\} and Melvin Ochieng and Clayton Onyango and Sandra Panchalingam and Adil Kalam and Fatima Aziz and Shahida Qureshi and Thandavarayan Ramamurthy and Roberts, \{James H.\} and Debasish Saha and Sow, \{Samba O.\} and Stroup, \{Suzanne E.\} and Dipika Sur and Boubou Tamboura and Mami Taniuchi and Tennant, \{Sharon M.\} and Deanna Toema and Yukun Wu and Anita Zaidi and Nataro, \{James P.\} and Kotloff, \{Karen L.\} and Levine, \{Myron M.\} and Houpt, \{Eric R.\}",

year = "2016",

month = sep,

day = "24",

doi = "10.1016/s0140-6736(16)31529-x",

language = "English",

volume = "388",

pages = "1291--1301",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier B.V.",

number = "10051",

}

Liu, J, Platts-Mills, JA, Juma, J, Kabir, F, Nkeze, J, Okoi, C, Operario, DJ, Uddin, J, Ahmed, S, Alonso, PL, Antonio, M, Becker, SM, Blackwelder, WC, Breiman, RF, Faruque, ASG, Fields, B, Gratz, J, Haque, R, Hossain, A, Hossain, MJ, Jarju, S, Qamar, F, Iqbal, NT, Kwambana, B, Mandomando, I, McMurry, TL, Ochieng, C, Ochieng, JB, Ochieng, M, Onyango, C, Panchalingam, S, Kalam, A, Aziz, F, Qureshi, S, Ramamurthy, T, Roberts, JH, Saha, D, Sow, SO, Stroup, SE, Sur, D, Tamboura, B, Taniuchi, M, Tennant, SM, Toema, D, Wu, Y, Zaidi, A, Nataro, JP, Kotloff, KL, Levine, MM & Houpt, ER 2016, 'Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study: a reanalysis of the GEMS case-control study', The Lancet, vol. 388, no. 10051, pp. 1291-1301. https://doi.org/10.1016/s0140-6736(16)31529-x

TY - JOUR

T1 - Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study: a reanalysis of the GEMS case-control study

AU - Liu, Jie

AU - Platts-Mills, James A.

AU - Juma, Jane

AU - Kabir, Furqan

AU - Nkeze, Joseph

AU - Okoi, Catherine

AU - Operario, Darwin J.

AU - Uddin, Jashim

AU - Ahmed, Shahnawaz

AU - Alonso, Pedro L.

AU - Antonio, Martin

AU - Becker, Stephen M.

AU - Blackwelder, William C.

AU - Breiman, Robert F.

AU - Faruque, Abu S.G.

AU - Fields, Barry

AU - Gratz, Jean

AU - Haque, Rashidul

AU - Hossain, Anowar

AU - Hossain, M. Jahangir

AU - Jarju, Sheikh

AU - Qamar, Farah

AU - Iqbal, Najeeha Talat

AU - Kwambana, Brenda

AU - Mandomando, Inacio

AU - McMurry, Timothy L.

AU - Ochieng, Caroline

AU - Ochieng, John B.

AU - Ochieng, Melvin

AU - Onyango, Clayton

AU - Panchalingam, Sandra

AU - Kalam, Adil

AU - Aziz, Fatima

AU - Qureshi, Shahida

AU - Ramamurthy, Thandavarayan

AU - Roberts, James H.

AU - Saha, Debasish

AU - Sow, Samba O.

AU - Stroup, Suzanne E.

AU - Sur, Dipika

AU - Tamboura, Boubou

AU - Taniuchi, Mami

AU - Tennant, Sharon M.

AU - Toema, Deanna

AU - Wu, Yukun

AU - Zaidi, Anita

AU - Nataro, James P.

AU - Kotloff, Karen L.

AU - Levine, Myron M.

AU - Houpt, Eric R.

PY - 2016/9/24

Y1 - 2016/9/24

N2 - Background Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). Methods GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. Findings We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2–96·0) at the population level, compared with 51·5% (48·0–55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6–80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. Interpretation A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. Funding Bill & Melinda Gates Foundation.

AB - Background Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). Methods GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. Findings We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2–96·0) at the population level, compared with 51·5% (48·0–55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6–80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. Interpretation A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. Funding Bill & Melinda Gates Foundation.

U2 - 10.1016/s0140-6736(16)31529-x

DO - 10.1016/s0140-6736(16)31529-x

M3 - Article

SN - 0140-6736

VL - 388

SP - 1291

EP - 1301

JO - The Lancet

JF - The Lancet

IS - 10051

ER -

Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study: a reanalysis of the GEMS case-control study

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