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