Highlights of RA3Rosalie Dhonukshe-Rutten
20 June 2011
Fundación para la Investigación Nutricional
Fundación para la Investigación Nutricional
Eurreca Chart
Two approaches to reach the objective:“Classical” “Association”
.
NIVs: ANR & INLx, specific for age, sex, life cycle
Scaling for age & sex: Based on body size (growth curves) &
energy intake (phys act)
RDAs, PRIs, DRIs, etc
Intake
Status / intake biomarker
Health or functional outcome
Required intake =Needs / bioavailab.
Bioavailability factor (apparent abs)
Maintenance body stores, growth, etc. RA3.2
RA3.3
RA3.1
RA3.4
RA3.2 RA3.4
RA3.6
RA3.5
What evidence is available?
Fe Zn Folate B12 IodineRA 3.1 Intake - Health
Intake - StatusStatus - Health
RA3.2 Factorial approach -skin-hair-cycle-faeces-urine-etcetera
Additional needs -pregnancy-lactation-growth
RA3.3 Bioavailability
RA3.4 Integrated model to calculate ANRs
1. What evidence is available?2. What evidence can be used?
How can the evidence be integrated?
Step 4Collection of available evidence
RA3.1Dose-response
RA3.2Classical studies
RA3.3Bioavailability
RA3.5Socioeconomic determinants
Databases, period
Cochrane Library, Medline, EMBASEuntil ~ Feb 2010
Pubmed/Medline~ juli 2010
Cochrane Library, Medline, EMBASEUntil July 2010
Medline, EMBASEJan 1990 – Aug 2010
Other search methods
Hand searching SR’s
Hand searching reference list of scientific reports on micronutrient reference values
Key inclusion criteria
• Apparently healthy• RA1 guidance• RCTs, (Nested Case) Cohorts, X-sectional studies
• Apparently healthy• ?
• Apparently healthy• RA1 guidance• RCT
• Published > 1990 • RA1 guidance• >100 subjects
Quality check Yes, 10% Yes, 10% Yes, 100%
Databases:Relevant papersExtracted data
EndnoteAccess
EndnoteExcel
EndnoteWord, other format
WebtoolExcel
Number of relevant studies identified and extracted
Dose-response Classical Bioavailability
Young Old Young Old Young Old
Vitamin B12 ~15 ~85 <5 ~20 0 ~10
Folate ~15 ~200 <5 ~20 12 ~15
Iodine ~135 ~70 ~50 ~15 - -
Zinc ~ 100 ~100 100 ~85 36 ~30
Iron >100 >100 ~10 ~60 ~60
What evidence can be used, and should be integrated?
Fe Zn Folate B12 IodineRA 3.1 Intake - Health
Intake - StatusStatus - Health
RA3.2 Factorial approach -skin-hair-cycle-faeces-urine-etcetera
Additional needs -pregnancy-lactation-growth
RA3.3 Bioavailability
RA3.4 Integrated model to calculate reference values
1. What evidence is available?2. What evidence can be used, should be integrated?
How can the evidence be integrated?
Highlights of results on Vitamin B12Association approach (RA3.1) - RCT’s
Intake-Status (RCT’s)Adults & Elderly
Highlights of results on Vitamin B12Association approach (RA3.1) - Observational
Intake-Status (Observational)Adults & Elderly
Step 5 Integration of evidenceAssociation useful for ANRs (yet identified)Example of vitamin B12
Association approach (RA3.1)
Study design # studies Status marker/Health outcome
Pooled estimate(95% CI)
Covariates used for stratification
Useful for deriving ANRs?
I – S: RCTs (all) 37 Serum/plasma vitamin B12
β=0.24(0.18 - 0.29)
Age <65 yrs
Age>=65 yrs
Yes
RCT’s (adults)
18 Serum/plasma vitamin B12
β=0.18(0.10 - 0.25)
RCT’s (elderly)
19 Serum/plasma vitamin B12
β=0.30(0.21 - 0.38)
I – S Obs (all) 20 Serum/plasma vitamin B12
β=0.09(0.04 - 0.14)
- Yes
S – H Obs 4 Cognition (dementia)
OR = 1.00(1.00 - 1.00)
- No
S – H Obs 4 Cognition (general score)
β=0.00(-0.00 - 0.00)
- No
S – H Obs 7 Vitamin B12Fracture risk
OR = 0.96(0.92 - 1.00)
- Yes?For elderly
Reflection on association useful for reference values
Vitamin B12: yes, mainly I – S adults and elderly (Oct 2012)
Iodine: yes, mainly for I – S all population groups (Oct 2012)
Iron: yes, I – S pregnant and lactating women (Dec 2012)
Zinc: yes, I – S infants, and adults & elderly; I – H infants (Dec 2012)
Folate: yes, I – S (Dec 2012)
Classical approachFactorial approach
Useful for ANR
Type of factorial estimate Nutrient Population
groupNumber of studies
Pooling of studies possible?
Indicator used
Key references
Maintenance/ balance ...
Skin
Hair
Menstrual cycle
Losses: bile, urine, faeces
Other
Classical approachFactorial approach
Useful for ANR?
Vitamin B12: no, not possible for any of the groups; although information available for additional needs for pregnant and lactating women
Iodine: yes, for all population groupsIron: yes, for total (including menstrual) losses,
and for growthZinc: undecided at this stageFolate: in progress
Classical approachBioavailabilityUseful for ANR?
Diet aspect studied (whole diet, meal or food item)
Nutrient Population group
Description # papers Average Absorption
Comments
Food item Vitamin B12
Adults and elderly
Specific food item: liver, meat, fish, egg, egg yolk, milk, bread
12 10-70% Few, old studies, specific food
items
Food item Folate In progress
Food item Zinc Test/ Whole/ Usual diet or meal
>40 19 – 65% In progress
Food item Iron Adults and elderly
Several types of diets, and single meals
13 1 – 16% In progress
Food item Iodine - - - 90% Not reviewed, key reference: Nath
1992, Vought and London 1967
Summary reflection on the two approaches
Infants Children & adolescents
Pregnant & lactating women
Adults & elderly
RA 3.1 I – H Zn, I, Fe I, Zn, Fe I, Zn, Fe I
I – S Zn, Fe I, Zn, Fe I, Zn, Fe I, B12, Zinc
S – H B12
RA3.2 Factorial approach Zn, Fe Zn Zn Zn, Fe
Additional needs Fe Fe I, Zn, Fe
RA3.3 Bioavailability Fe Fe Fe B12, I, Fe, Zn, FA
Step 6
Vitamin B12
Current intake scenario• ln(median intake) = 1.60• ln(median status) = 5.72 • median intake = 5 µg/day• median status = 300 pmol/L
Alternative intake scenario• ln(median intake) = 2.53• ln(median status) = 5.86• median intake = 12.5 µg/day• median status = 351 pmol/L
By increasing the median vitamin B12 intake with 153% the percentage inadequate intake is expected to decrease from 5.2 % to 2.5 %
regression coeff. 0.16correlation coeff. 0.29
5.2 %2.5 %
x = study medians95% confidence ellipses
150pmol/L
1) scaling based on metabolic turnover
2) scaling by 2-step extrapolation method
RepresentativeCalculated Adult surface areachild
reference = reference x Representativeintakechild intake surface areaadult
ANRchild = ANRadult x F
F = (weightchild/weightadult)0.75 x (1+growth factor)
Figure 1: Growth factors (WHO 1985)
Scaling method within EURRECA
Microsoft Excel Worksheet
Step 7
Evidence for policy options
RA 3.5General Objective
Collate and compare scientific evidence on determinants of low
micronutrient intake and status for priority micronutrients in Europe
What is the relationship between socioeconomic and cultural factors
micronutrient intake and status of EURRECA’s prioritized micronutrients
among European population groups?
Research question:
IMR, FIN, WULS-SGGW, KU Leuven, UCLAN, OBU, WHO & WU
RA 3.5 Preliminary Results: Males
CH (2001) IE (2003) NL (2003) NL (2000) ES (2001) UK, m&f (1999)
-35%
-30%
-25%
-20%
-15%
-10%
-5%
0%
5%
Calcium
Education Occupation IncomeStudy
Dif
fere
nc
es
in in
tak
e %
(lo
w-h
igh
)/h
igh
CH (2001) IE (2003)-35%
-30%
-25%
-20%
-15%
-10%
-5%
0%
5%
Vitamin D
Indication for inadequacy: intake in lower SES group < ANR
IE (2003) NL (2003) ES (2001) UK, m&f (1999)
-35%
-30%
-25%
-20%
-15%
-10%
-5%
0%
5%
Iron
Education Occupation Income
Dif
fere
nc
es
in in
tak
e %
(lo
w-h
igh
)/h
igh
RA 3.5 Preliminary Results: Females
FI (1996) Scotland (1991)
IE (2003) NL (2003) NL (2000) ES (2001) UK, m&f (1997)
UK, m&f (1999)
-35%
-30%
-25%
-20%
-15%
-10%
-5%
0%
5%
Vitamin C
Study
Take home message
• Much and great work has been done within RA3!
• The results provide good building blocks for setting reference values, modelling:– New evidence: I – S (meta analysis, stochastic
modelling)– Complementary: classical approach
• Evidence-based, harmonized, transparent
• Continue this successful work!
Acknowledgement partners
Fundación para la Investigación Nutricional
Fundación para la Investigación Nutricional
Backup RA2.7
RA 2.7 Results: Males
RA 2.7 Results: Females
Example scientific result : Immigrants & intake adequacy for selected micronutrients
Country Ethnic group Population nIntake
methodmean SD % < ANR WHO % < ANR NORDIC
Folate (mcg) 320mcg 200mcg
Slovakia Roma/Gypsy adult 82 FFQ 156.0 7.0 100 100
UK South Asian adult 123 4d EFR 137 62.3 99.8 84.4
UK South Asian adult 100 12d 24HR 180 50 99.7 99.7
Males Slovakia Roma/Gypsy adult 68 FFQ 160 7.0 100 100
UK South Asian adult 119 4d EFR 215 103 84.6 44.2
Vit B12 (mcg) 2.2mcg 1.7mcg
Females Greece Albanian prenatal 908 30d EFR 1.8 0.13 99.9 22.1
2.0 mcg 1.4 mcg
UK South Asian adult 123 4d EFR 1.8 1.4 55.6 38.9
Calcium (mg) 833 mgAdequate Intake
800 mg
Females Slovakia Roma/Gypsy adult 82 FFQ 641 237 79.1 NA
UK South Asian adult 100 12d 24HR 759 229 62.7 NA
UK Pakistani adult 50 FFQ 601 288 79.0 NA
Males Slovakia Roma/Gypsy adult 68 FFQ 676 376 66.2 NA
UK Pakistani adult 34 FFQ 605 277 79.5 NA
Iron(mg) Mean intake as %
INL98 (29.4 mg )
Mean intake as % INL98 (15 mg )
Females Slovakia Roma/Gypsy adult 82 FFQ 14.4 4.5 49.0 96
UK South Asian adult 100 12d 24HR 10.8 3.1 36.7 72
UK Pakistani adult 50 FFQ 14.1 48.0 94
UK Afro-Caribbean adult 147 FFQ 10.1 34.4 67.3
Example scientific result:Prevalence of inadequate folate intake (% population below ANR) in Europe by
gender and population group.
≤ 10%
11 to 20%
21 to 30%
31 to 40%
41 to 50%
Adult males(EAR=200 µg/day)
Elderly males(EAR=200 µg/day)
Adult females(EAR=200 µg/day)
Elderly females(EAR=200 µg/day)
Nog doen
Dia 9, 14, 17, 20, 21, 28, 29
11 eruit laten of simpel als voorbeeld even aan herinneren