1. The Global Enteric Multi-Center Study
(GEMS): Etiology & Burden of Moderate &
Severe Diarrheal Disease in Africa & Asia
Myron M (Mike) Levine, MD, DTPH
Grollman Distinguished Professor & Director
Center for Vaccine Development,
University of Maryland School of Medicine
Baltimore, MD 21201, USA
PAS Annual Meeting, April 30, 2012
CVD
Boston, MA, USA

2. UN Millenium Development Goal # 4 aims to diminish
mortality in children < 5 years of age by 67% by 2015
Of the 35 countries with the
highest under-five mortality,
34 are in sub-Saharan Africa!!!
(State of the World’s Children, UNICEF 2011)

3. Deaths
among
children < 5
years of age
(CHERG
data)
RE Black et al,
Lancet 2010
CVD

4. Clinical syndromes
“Simple” gastroenteritis
Watery diarrhea, mucus, some
vomiting, low-grade fever, malaise,
anorexia; dehydration in infants
Profuse watery diarrhea
Purging of voluminous rice water stools;
dehydration of older children & adults
Dysentery
Blood & mucus in diarrheal stools
Persistent diarrhea CVD
Continues > 14 days, unabated

5. Some limitations of earlier studies
• Few studies from countries with high child mortality
• Very few studies from sub-Saharan Africa
• Typically only one site studied per report
• Often limited to children < 24 months of age
• Most had short surveillance (only 6-24 calendar
months; too limited to detect cyclical patterns)
• Failure to enroll and study matched controls
• Lack of census data or linkage to a DSS
• Health care utilization patterns not known
• Incomplete survey of etiological agents
• Insensitive microbiological methods
• Strains not characterized for serotype, genotype, etc.
• No follow-up of cases & controls

6. GLOBAL ENTERIC MULTI-CENTER STUDY (“GEMS”)
Diarrheal disease in infants & young children in developing countries
Project Funded by Bill & Melinda Gates Foundation
The GEMS Leadership Team:
Coordinating Investigator
Myron M. (Mike) Levine, M.D., D.T.P.H.
Center for Vaccine Development,
University of Maryland School of Medicine
Principal Investigator, epidemiology & clinical
Karen L. Kotloff, M.D.
CVD Principal Investigator, microbiology
James P. Nataro, M.D., Ph.D.
(since 9/2010, Professor & Chair, Dept. of Pediatrics, U. of Virginia)

7. • Common protocol to study moderate & severe diarrhea (MSD)
• Rigorous epidemiologic case/control & microbiologic design
• Defined population under demographic surveillance
• 3 age strata: 0-11 mos; 12-23 mos; 24-59 mos
• Health Services Utilization & Attitudes Survey (HUAS); 1000/site
• 600 analyzable cases & > 600 analyzable matched controls per
age group, per each of 7 sites, over 3 years
• Record all diarrhea and all MSD cases coming to sentinel sites
• Even sampling throughout the year (8-9 cases per age stratum,
per fortnight, throughout the enrollment period)
• AFRICA & ASIA; rural & urban; high & low HIV; high & low malaria
• Record specific clinical syndromes
• Utilize modern molecular diagnostic tools
• Expanded etiology; serotypes; antigenic types; genotypes
• 60-DAY FOLLOW-UP VISITS of cases & controls
– Detect deaths; nutritional consequences; (persistent diarrhea)
• Water/sanitation risk factor data & economic burden data
• SPECIMEN & STRAIN REPOSITORY

8. 4 GEMS Sites in Sub-Saharan Africa
CDC/KEMRI, Kisumu, Kenya PI – Robert Breiman
MRC Unit, Basse, Gambia PI – Debasish Saha
Richard Adegbola
Jahangir Hussein
CISM, Manhiça, Mozambique PI – Pedro Alonso
CVD-Mali, Bamako, Mali PI – Samba Sow
3 GEMS Sites in South Asia
Aga Khan University, Pakistan PI – Anita Zaidi
NICED, Kolkata, West Bengal, India PI- Dipika Sur
ICDDR,B: Mirzapur, Bangladesh PI- ASG Faruque

9. Salient features of the seven GEMS-1 sites
Manhiça, Mirzapur,
Basse, Bamako, Kisumu, Karachi, Kolkata,
Site Mozam- Bangla-
Gambia Mali Kenya Pakistan India
bique desh
Coastal
Mostly Mostly
Setting Very rural Urban Rural fishing Urban
rural rural
villages
National
67.5 113.7 103.8 53.5 52.5 65.3 49.1
IMR*
DSS
annual 157,726 210,425 84,206 141,628 254,751 252,346 194,172
pop’n (28,898) (32,526) (16,657) (23,294) (24,077) (24,792) (12,885)
(< 5 yrs)
Malaria
preva- Moderate Moderate Moderate Mod-
Low Low Low
lence (falling) (falling) erate
HIV
preva- Low Low High High Low Low Low
lence
* IMR, infant mortality rate = deaths of infants 0-11 months of age per 1000 live births

10. Some GEMS assumptions
• A limited number of etiologic agents may be responsible
for a disproportionately large fraction of MSD
• MSD seen at SHCs is a proxy for fatal disease in the
community
• The appropriate epidemiologic design for identifying the
relative importance of pathogens associated with MSD
is a matched case/control study (MSD uncommon)
• We can standardize clinical and lab methods across
sites and maintain GCP, GCLP and Quality Control
• Making a single 60-day post-enrollment visit to case &
control households creates prospective mini-cohorts
• Results will facilitate the setting of investment &
intervention priorities

11. Study Advisories
Steering Committee on Epidemiology/Clinical Issues
Fred Binka (Ghana), Eric Mintz (CDC), Paul Stolley (UM), John
Clemens (IVI), Halvor Sommerfelt (Bergen), Dani Cohen (Tel Aviv U),
Roger Glass (Fogarty)
Steering Committee on Microbiologic Issues
Roy Robins-Browne (U of Melbourne), Philippe Sansonetti (Institut
Pasteur), Patrick Murray (NIH), Duncan Steele (PATH)
Steering Committee on Biostatistical Issues
Larry Moulton (JHU), Barry Graubard (NCI), Peter Smith (LSTMH),
Janet Wittes (Statistics Collaborative), William Pan (Duke)
Steering on Nutritional Issues
Reynaldo Martorell (Emory), Claudio Lanata (IIN), Rebecca Stoltzfus
(Cornell)
Consensus -- Case/control protocol & microbiologic methods &
analytical strategies were finalized after consultations with the SCs
Reference Laboratories

12. MSD case eligibility & enrollment
• Age 0-59 mos. & from DSS
• Seeking care at a sentinel Health Center (SHC)
• Diarrhea (> 3 loose stools in previous 24h)
• Diarrhea-free for 7 days before current episode
• Episode began within 7 days of enrollment
• Diarrhea is moderate or severe, i.e., has > 1 of:
– Moderate/severe dehydration:
• Sunken eyes
• Loss of skin turgor
• IV rehydration required
CVD
– Dysentery (gross blood & mucus)
– Hospitalized (clinician’s judgment)

13. Selection of controls
• Community controls randomly selected using DSS database
• 1-3 controls/case
• Matched to case by:
– Age (strata are respected)
• 0-11 mos: +2 months
• 12-59 mos: +4 months
– Gender
– Same or nearby village
– Within 14 days of presentation of case
• No diarrhea within 7 days of enrollment
• Provides stool sample of acceptable quality
• Informed consent

14. Microbiology work flow
CVD

15. Full 36 mos. of
ALL SITES GEMS data
Controls enrolled Controls enrolled
13,125
6810 6315
A
AS
Cases enrolled 9524 Cases enrolled
RIC
5282 (65%) 4242
IA
MSD eligibles 14,753 MSD eligibles
AF
9149 (21%) 5604
All cases of diarrhea All cases of diarrhea
seen at SHCs 71,364 seen at SHCs
35,984 35,380
CYO < 60 mos in DSS CYO < 60 mos in DSS
483,627
295,164 188,463

16. Pathogens (including Giardia) identified in stool
specimens from cases and controls during the
first 2 years of GEMS
No. of 4 African sites 3 Asian sites
pathogens
identified Cases (%) Ctrls (%) Cases (%) Ctrls (%)
At least 1 79 71 83 70
At least 2 37 29 47 32
At least 3 10 7 16 10

17. Pathogen isolations, India site, 12-23 months age group.
588 cases & 598 controls (3-year data)
Pathogen Cases Pathogen Cases
Rotavirus 151 Astrovirus 19
Giardia 138 tEPEC 18
Cryptosporidium 98 ETEC - LT only 17
Campylobacter jejuni 83 E. histolytica 14
EAEC 72 Adenovirus non-40-41 11
Norovirus GII 51 Campylobacter coli 5
Shigella 40 Norovirus GI 4
Adenovirus 40/41 29 Aeromonas 2
ST-only ETEC 26 EHEC 2
Sapovirus 24 Non-typhoidal Salmonella 1
V. cholerae O1 21
ETEC - LT/ST 21
aEPEC 21

18. Pathogen isolations, India site, 12-23 months age group.
588 cases & 598 controls (3-year data)
Pathogen Cases Ctrls Pathogen Cases Ctrls
Rotavirus 151 13 Astrovirus 19 13
Giardia 138 173 tEPEC 18 18
Cryptosporidium 98 60 ETEC - LT only 17 21
Campylobacter jejuni 83 76 E. histolytica 14 4
EAEC 72 82 Adenovirus non-40-41 11 11
Norovirus GII 51 33 Campylobacter coli 5 9
Shigella 40 7 Norovirus GI 4 12
Adenovirus 40/41 29 4 Aeromonas 2 5
ETEC - ST-only 26 9 EHEC 2 0
Sapovirus 24 15 Non-typhoidal Salmonella 1 2
V. cholerae O1 21 2
ETEC - LT/ST 21 6
aEPEC 21 66

19. Attributable Fraction (AF)
Grappling with the issue of enteric pathogens in
matched controls without diarrhea
• Fraction of all MSD (moderate & severe diarrhea)
cases attributable to (presumably caused by) a
particular pathogen
• Fraction of MSD cases or MSD incidence rate that
could theoretically be eliminated if the pathogen were
eliminated
Grappling with the issue of multiple enteric
pathogens in cases & controls
• Bruzzi et al (AJE 1985) allows AF to be calculated while
CVD
taking into account the presence of other pathogens
• Allows AF for a group of pathogens (e.g., “Top 5”)

20. India, age 12-23 months:
588 cases, 598 controls (3 years of data)
Cases Ctrls Adj
With With Adj Attrib
Pathogen Pathogen Pathogen OR p-value AF Cases
Rotavirus 151 13 21.1 <0.0001 0.278 144
Cryptosporidium 98 60 2.1 0.002 0.088 52
Shigella 40 7 14.6 <0.0001 0.063 37
LT/ST or ST-only 47 15 3.8 <0.0001 0.059 35
Adenovirus 40/41 29 4 11.1 <0.0001 0.045 26
V. cholerae O1 21 2 10.4 0.001 0.032 19
E. histolytica 14 4 5.4 0.045 0.019 11

21. Pathogen-specific adjusted attributable fractions,
0-11 months age group, “Top 5” analysis (3 yrs of data)
0-11 m Gambia Kenya Mali Mozam India Bangla Pakistan
Total cases 400 673 727 374 672 550 633
#1 RV RV RV RV RV RV RV
(23%) (19%) (21%) (32%) (28%) (17%) (23%)
#2 Crypto Crypto Crypto Crypto Crypto Shigella Aeromon
(11%) (9%) (14%) (14%) (13%) (13%) (11%)
#3 Noro-GII ETEC ST or ETEC ST or ETEC ST or Adeno C. jejuni ETEC ST or
(7%) LT/ST (6%) LT/ST (4%) LT/ST (3%) 40/41 (4%) (10%) LT/ST (7%)
#4 ETEC ST or tEPEC Adeno Adeno ETEC ST or Aeromo Shigella
LT/ST (4%) (5%) 40/41 (2%) 40/41 (2%) LT/ST (3%) (10%) (7%)
#5 Shigella Shigella Shigella Crypto Crypto
(4%) (4%) (2%) (6%) (4%)
“Top 5” - %
of all cases 47% 40% 38% 47% 46% 49% 46%

22. Pathogen-specific adjusted attributable fractions
12-23 months age group, “Top 5”analysis (3 yrs of data)
12-23 m Gambia Kenya Mali Mozam India Bangla Pakistan
Total cases 455 410 682 194 588 476 399
#1 RV RV RV Crypto RV Shigella Shigella
(17%) (14%) (12%) (9%) (24%) (53%) (11%)
#2 Shigella Crypto Crypto ETEC ST or Crypto RV Aeromon
(12%) (8%) (4%) LT/ST (9%) (9%) (17%) (11%)
#3 Noro-GII ETEC ST or ETEC ST or Shigella Shigella Aeromon RV
(8%) LT/ST (7%) LT/ST (3%) (6%) (6%) (11%) (10%)
#4 Crypto Shigella Shigella RV ETEC ST or EAEC Crypto
(8%) (4%) (2%) (5%) LT/ST (6%) (9%) (8%)
#5 ETEC ST or NTS
-
C. jejuni Noro-GII V. chol V. chol
LT/ST (6%) (4%) (2%) (5%) O1 (1%) O1 (8%)
“Top 5” - %
all cases
45% 34% 20% 36% 45% 76% 47%

23. Pathogen-specific adjusted attributable fractions
24-59 months age group. “Top 5” analysis (3 yrs of data)
24-59 m Gambia Kenya Mali Mozam India Bangla Pakistan
Total
cases
174 393 624 112 308 368 226
#1 RV Shigella RV Shigella RV Shigella Aeromonas
(13%) (9%) (3%) (17%) (14%) (69%) (25%)
#2 Shigella ETEC ST or E. histolyt V. chol O1 Shigella Aeromon V. chol O1
(13%) LT/ST (5%) (2%) (8%) (11%) (5%) (13%)
#3 ETEC ST or NTS Shigella
-
C. jejuni V. chol O1 C. jejuni
LT/ST (8%) (4%) (2%) (10%) (3%) (12%)
#4 Noro-GII RV
- -
V. chol O1 NTS Shigella
(8%) (3%) (8%) (2%) (9%)
#5 -
Crypto
- -
ETEC ST or
-
ETEC ST or
(3%) LT/ST (7%) LT/ST (5%)
“Top 5 - %
all cases 38% 22% 7% 24% 44% 77% 51%

24. Some broad observations
• “Top 5” pathogens predominate but differ by age stratum
• Specific effective interventions against a small number of
pathogens can have a notable impact
• New potential priorities identified:
– Cryptosporidium
– C. jejuni and perhaps Aeromonas in Asia
– Adenovirus 40,41? NV GII?
• WHO pathogen priority list corroborated
– Rotavirus, ETEC, Shigella, V. cholerae O1
• A proportion of diarrhea cases do not have attribution
– Other etiologies? Promiscuous antibiotic usage?
CVD
• All sites & ages, Giardia associated with a significantly
lower likelihood of MSD (i.e., appears “protective”)

25. Probability of MSD case visiting SHC
within 7 days of onset (“r”)
r is estimated
• From pooled HUAS-lite data
• Using life table (Kaplan-Meier) analysis, to
adjust for HUAS-lite interviews occurring
within 7 days of onset of diarrhea
CVD

26. Annual burden (cases & incidence) of adjusted pathogen-attributable
MSD, by age, in children age 0-59 mos. in rural Gambia
0-11 m 12-23 m 24-59 m
N=5708 N=6230 N=17,139
Total MSD cases 789 1232 513
Adjusted “Top 5” attributable cases 369 561 196
Total MSD rate/100 CYO 13.8 19.8 3.0
“Top 5” attributable MSD rate/100 CYO 6.5 9.0 1.1
Rotavirus/100 CYO 3.2 3.4 0.4
Shigella/100 CYO 0.5 2.3 0.4
Cryptosporidium/100 CYO 1.6 1.5 -
ETEC LT/ST or ST-only/100 CYO 0.6 1.1 0.3
Norovirus GII/100 CYO 1.0 0.7 0.1
Adenovirus 40,41/100 CYO 0.3 0.5 -

27. Annual burden of adjusted pathogen-attributable MSD, by age, in
children age 0-59 mos. in Pakistan
0-11 m 12-23 m 24-59 m
N=4045 N=4653 N=15,827
Total MSD cases 1121 816 452
Adjusted “Top 5” attributable cases 514 381 228
Total MSD rate/100 child years 27.7 17.5 2.9
“Top 5” attributable MSD rate/100 CYO 12.7 8.2 1.4
Rotavirus/100 CYO 6.6 1.8 -
Aeromonas/100 CYO 2.8 1.9 0.7
Shigella/100 CYO 1.9 2.0 0.2
Vibrio cholerae O1/100 CYO 0.9 1.3 0.4
Cryptosporidium/100 CYO 1.4 1.4 -
ETEC LT/ST or ST/100 CYO 2.1 - 0.2
Campylobacter jejuni 1.8 - 0.3
Adenovirus 40/41 0.4 0.6 -
Astrovirus 0.8 - -

28. Annual burden of adjusted pathogen-attributable MSD, by age, in
children age 0-59 mos. in Kenya
0-11 m 12-23 m 24-59 m
N=3159 N=4746 N=13,698
Total MSD cases 1125 730 690
Adjusted “Top 5” attributable cases 447 251 155
Total MSD rate/100 child years 35.6 15.4 5.0
“Top 5” attributable MSD rate/100 CYO 14.2 5.3 1.1
Rotavirus/100 CYO 6.7 2.1 0.2
Cryptosporidium/100 CYO 3.3 1.3 0.1
ETEC LT/ST or ST-only/100 CYO 2.3 1.1 0.2
Shigella/100 CYO 1.5 0.7 0.5
tEPEC/100 CYO 1.7 0.5 -
Non-typhoidal Salmonella/100 CYO - 0.6 0.2
Adenovirus 40,41/100 CYO 0.7 - -
Entameba histolytica/100 CYO - 0.2 -

29. Preliminary analysis
of mortality data
from 24 months of GEMS
Pakistani child with
severe diarrheal
dehydration
CVD

30. Cases Controls
Died Survived CFR Died Survived CFR
Mozambique
50 630 7.4% 11 1277 0.9%
[RR 8.6 (4.5, 16.4)]*
Kenya
53 1428 3.6% 11 1877 0.6%
[RR 6.1 (3.2, 11.7)]*
Gambia
39 991 3.8% 7 1563 0.5%
[RR 7.5 (3.8, 18.9)]*
Mali
23 2010 1.1% 5 2059 0.2%
[RR 4.7 (1.8, 12.3)]*
Pakistan
16 1241 1.3% 1 1835 0.1%
[RR 23.4 (3.1, 176.0)]*
Bangladesh
7 1387 0.5% 1 2464 0.04%
[RR 12.4 (1.5, 100.5)] *
India
2 1566 0.1% 1 2013 0.1%
[RR 2.6 (0.2, 28.3)**
Total 190 9253 2.0% 37 13088 0.3%
[RR 7.1 (5.0, 10.1)* * p<0.01; **p=0.42

31. Summary of mortality data
• An episode of MSD is associated with a 6- to 7-
fold increase in the risk of death within the
ensuing ~ 60 days compared to matched controls
– Range 2.6-fold in India to 23.4-fold in Pakistan
• When deaths occurred:
– 35% of deaths occurred within 7 days of enrollment
– 65% of deaths occurred > 7 days after enrollment
– 33% of deaths occurred > 21 days after enrollment
• Where deaths occurred:
– 44% of cases died at a medical facility
• 26% of cases died during initial SHC encounter
CVD – 56% cases died at home or outside a medical facility

32. Risk factors for fatal disease
In a multivariate model, case fatality was
directly correlated with:
• Younger age
• High HIV prevalent sites (Kenya & Mozambique)
• Offering less than usual to drink during diarrhea
• Low WAZ at enrollment
• Isolation of tEPEC, Cryptosporidium

33. Case fatality by site and age stratum
10 Cases Controls RR
9 0-11m 107 22 5.9
8
12-23m 60 12 6.8
% case fatality
7
6
24-59m 23 3 13.5
5
4
3
2
1
0
Gambia Mali Mozambique Kenya India Bangladesh Pakistan
CVD

34. Percent isolation of certain pathogens in fatal and
non-fatal MSD cases in infants, by age trimester
35 p<0.0001
p=0.06
30
Fatal cases
25
p=0.06 Survived cases
20
p=0.01
p=0.09
p=1.0
15 p=0.25
p=0.71
10 p=0.50
5
0
0-3 mths 4-7 mths 8-11 mths 0-3 mths 4-7 mths 8-11 mths 0-3 mths 4-7 mths 8-11 mths
ETEC-ST tEPEC Cryptosporidium

35. Percent Cryptosporidium isolation in fatal vs
30
non-fatal MSD cases in toddlers
25
25%
20
p=0.0024 Fatal MSD
15
cases
11.4% Survived
10
MSD cases
5
0
12-23 mos

36. An episode of MSD significantly impacted
the linear growth of children
• At enrollment, cases were comparable to
controls in stature in both continents and all
age groups
• MSD cases had worse linear growth
outcome than controls (comparing
anthropometric measurements at enrollment &
60 days)
• Africa (-0.11, p = <0.0001)
CVD
• Asia (-0.07, p=<0.0001)

37. 0-11 months AFRICA
0-11 months 12-23 months
12-23 months 24-59 months
24-59 months
0
(Cases = closed circles ; Controls=open circles )
(HAZ cases = slope of HAZ change between enrollment and 60-day follow up in cases)
-0.2
(HAZ ctrls = slope of HAZ change between enrollment and 60-day follow up in controls)
( slope = difference between mean HAZ cases and HAZ ctrls
-0.4
p=NS
-0.6
 Slope p<0.05
-0.8
z score
HAZ ctrls P<0.05
 Slope <0.05
-1 p=NS  Slope p<0.05
-1.2 HAZ cases p<0.05 p=NS
HAZ ctrls p<0.05 HAZ ctrls p<0.05
-1.4 p<0.05
HAZ cases p<0.05 HAZ cases p<0.05
-1.6
-1.8 P=NS p=NS
-2
Enrollment Follow-up Enrollment Follow-up Enrollment Follow-up

40. Serotype Cases % of all case isolates
Serotypes of Shigella
S. dysenteriae (any serotype) 55 4.9
S. boydii (any serotype) 62 5.5
isolated from 1124
S. sonnei 269 23.9 GEMS
S. flexneri 1a 3 0.3 cases:
S. flexneri 1b 87 7.7
S. dysenteriae – 4.9%
S. flexneri 2a 229 20.4
S. flexneri 2b 121 10.8
S. boydii – 5.5%
S. flexneri 3a 105 9.3 S. sonnei – 23.9%
S. flexneri 3b 1 0.1 S. flexneri – 65.7%
S. flexneri 4 6 0.5
S. flexneri 4a 24 2.1
S. flexneri 4b 1 0.1 types 2a + 3a + 6
S. flexneri 4c 1 0.1 comprised 457 of 738
S. flexneri 5a 0 0.00
S. flexneri strains
S. flexneri 5b 3 0.3
S. flexneri 6 123 10.9
S. flexneri X 9 0.8 2a+3a+6 + S. sonnei
S. flexneri Y 3 0.3 = 65% of all isolates
“1c” (S. flexneri 7) 22 2.0

41. Summary comments
Important insights
• A small number of pathogens account for ~
one-half of the MSD burden in the first 2
years of life (when mortality risk is highest)
• MSD is associated with a 7-fold increase in
the risk of death over the ensuing 60 days
• Whereas MSD cases & controls are equally
stunted upon enrollment, MSD accelerates
stunting over the next 60 days
CVD

42. Proposed actions based on GEMS data
• Implement licensed rotavirus vaccines
into the EPI of countries in sub-Saharan
Africa and South Asia
• Implement cholera vaccines in high risk
pre-school populations in young children
• Given the major role identified for
Cryptosporidium as a cause of MSD, invest
to develop:
– Simple rapid diagnostics
– Effective therapy
CVD – Vaccines
• Implement WASH interventions

43. ACKNOWLEDGMENTS
It takes a global village of
investigators, colleagues and
wise advisers to complete a
CVD study like the GEMS

44. GEMS Investigators, Mozambique, 2010
CVD

45. International Strategic Advisory Committee
(GEMS-ISAC)
Co-Chairs: Prof George Griffin, UK; Prof Zulfiqar
Bhutta, Pakistan; Prof Fred Binka, Ghana
Members: G Armah (Ghana), MK Bhan (India), RE
Black (USA), J Breman (USA), WP Chaicumpa
(Thailand), T Corrah (Gambia), A Cravioto
(Bangladedh), V Curtis (UK), G Dougan (UK), K
Earhardt (USA/India), A Grange (Nigeria),G Kang
(India), C Lanata (Peru), R Martorell (USA), C
Morel (Brazil), C Murray (USA), B Nair (India), M
CVD O’Ryan (Chile), P Sansonetti (France), P Smith
(UK), M Tanner (Switzerland),

46. Acknowledgments
Many thanks to the superb investigators and staff at each
study site, collaborating center, steering committee, and at
the CVD coordinating center, to the families who have
graciously participated in this study, and to the Bill &
Melinda Gates Foundation for financial support.
CVD