Evidence for health effects of what we eat: how to integrate - PowerPoint PPT Presentation

Evidence for health effects of what we eat: how to integrate findings from intervention and observational studies? Prof Pieter van 't Veer, PhD Division of Human Nutrition Wageningen University Carla Dullemeijer, Olga W Souverein, Esmée L Doets, Hilko van der Voet, Janneke P van Wijngaarden, Waldo J de Boer, Maria Plada, Rosalie AM Dhonukshe-Rutten, Paulette in `t Veld, Adrienne EJM Cavelaars, Lisette CPGM de Groot

Domain of this presentation • Knowledge of health effects of what we eat (somehow) integrated in reference values • Nutrient reference values serve as tools for evaluating usual intake of individuals / populations, to provide advice / propose policies • Focus on deriving nutrient reference values • EURRECA NoE (2007-12): micronutrients

Reference values for populations and individuals ANR, EAR (Estimated Average Requirement) A daily nutrient level estimated to meet the requirements of half the healthy individuals in a particular life stage and gender group. RDA, RDI, INL 97.5 (Recom- mended Dietary Intake) Biological variation: susceptibility The average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97–98 per cent) healthy individuals in a particular life stage and gender group. *source: FNB:IOMFood and Nutrition Board: Institute King et al. 2007 of Medicine DRI process

Nutritional adequacy – the health criterion (Gibney) Criterion of adequacy / health criterion determined by the level of intake that � Prevents deficiency symptoms Traditional � Optimizes body stores of a nutrient � Optimizes some biochemical or physiological function Physiological / nutritional approach � Minimizes a risk factor for chronic disease Epidemiology / public health perspective � Minimizes the incidence of disease (From Introduction to Human Nutrition, Gibney et al;(ed))

Methodological scope of presentation (data from Eurreca on B12 preliminary & for illustration) Three “dimensions” of studies on requirements � Two concepts Dose response Balance � Two applications Individual Population � Two study designs Intervention Observational

Study concept: “Dose-response” & “balance” On each point on the line, a steady state Dose-response (balance) is assumed. data from one How to construct the subject line? Health criterion Normal function (physiological Symptoms, adverse effects requirement) Required intake (micro)nutrient intake

Dose-response: individ. requirements & popul. ref. intake P 97.5 P 2.5 Marker of ‘status’ Health criterion value (physiological requirement) Distribution of required Q1: Given an intake agreed value for the health criterion, how much should a (population of) individual(s) eat Intake required to attain to attain that level of status marker value? ANR SD req

Balance approach (“in = out”): example vit. B 12 Sum of losses (faeces, urine, skin, …., periods) + need for growth (fetus, child, pregnancy, lactation, ..) ANR ≡ Bioavailability Factor � Health criterion • Netherlands: Maintenance liver stores B 12 > 500 � g • France: Compensation of losses via bile • USA: maintenance haematological status in pernicious anaemia patients (stable Hb, normal MCV & normal reticulocyte response) � Bioavailability factor • All countries, assessed by faecal excretion, whole body counting � Add CV=10% to allow for variation of ANR between subjects

Methodological scope of presentation (data from Eurreca on B12 preliminary & for illustration) Three “dimensions” of studies on requirements � Two concepts Dose response Balance � Two applications Individual Population � Two study designs Intervention Observational

Study design: Evidence pyramid (strength of...) Evidence integrated per study type in pyramid (meta- & pooled analyses) Intervention studies, � RCT-principle (“causality”) (e.g., Cochrane approach) Observational studies “epidemiology” To be (e.g. WCRF global report diet & cancer) inserted � Prospective cohort (-nested case control) � Case control studies (in dynamic population) � Cross-sectional studies (“descriptive”) � Ecological studies (“aggregate”)

Methods relevant to assess requirements (Gibney) � Deprivation studies (‘depletion-repletion’; haem.status PA) � Radioactive tracer studies (‘turnover’, ‘bioavailability’) � Balance studies (input = loss in dynamic steady state) � Factorial meth. ( Σ losses + needs for growth: bile losses) � Tissue levels (e.g. liver stores of vitamin B12) � Biochem markers (serum/plasma B12, holoTC) � Biological markers (early, interm, late endp., e.g. MMA) � Animal experiments (all) (From Introduction to Human Nutrition, Gibney et al;(ed))

Cross-tab “pyramid” by “data for requirements” Methodology Interven- Prosp. Case- Cross- Eco- (Gibney) tion cohort control section logical Depletion-repletion + (no ran- dom alloc) Radio-active tracers + Balance studies + Factorial methods + Tissue levels + Biochemical markers + (RCT) + Biological markers + (RCT) + Animal experiments + (RCT) Red: Mainly used in setting reference values (data limited) Box: Seldomly used (plenty of data available) � OPPORTUNITY!! NB: “Nutritional status” subjects in RCT <represent. than X-sectional

Study methods by “concept” and “design” Study concept Intervention design Observational design (manipulates the exposure) (assesses the exposure) Balance Depletion-repletion Radioactive tracers (whole i.e. input = output (under (quasi experimental) body count) steady state condition) Factorial methods (faeces, skin, etc) Tissue levels (liver) Independent Example B 12 Maintenance haematological Biliary stores > 500ug (NL) approaches � status in pernicious anaemia Biliary losses (FR) patients (stable Hb, normal Same results MCV & normal reticulocyte (ANRs)? response) (US) Dose-response RCT, using supplements, Cross-sectional studies, between intake and enriched foods, whole diets intake by dietary outcome (after reaching assessment Same markers, different steady state condition) designs: How to integrate? Examples B 12 Relation to serum/plasma vitB 12 levels, methylmalonic acid (MMA), serum/plasma holo-transcobalamin (holoTC)

Evidence base “balance approach” (B 12 ) Method Refs, yr N total , sex Pop, remarks Conclusions Healthy subjects daily loss of total Whole body 6 13 body pool = 0.15% counting 1960-68 male (SE=0.01%) healthy, cholecyst- biliary loss roughly Bile losses 6 38 ectomised, post- estimated as 1.4 1956-91 mixed, not operative, with(hout) ug/day specified pernicious anaemia pernicious anaemia At 1.4 ug/day 4/7 Maintenance 1 7 patients subjects reached a haematological 1958 sex not normal status specified haematological status ≈ 75 Healthy subjects. BF = 50% Bioavailability 11 Foods raw/cooked, range 5-65% 1959-01 mixed, most high/low B12 content High dose: less unspecified

Current estimates of ANR: error in estimates � Netherlands • ANR = (minimum liver store) x (loss by whole body counting) / BF. • ANR = (>500ug) * (0.15%) / (50%) = 2 ug/d • CV(estimate) ≈ 7% / ≈ 10% � totals ≈ 12% � France • ANR = (biliary loss & account for reabsorption via IF) / BF = 2 ug/d • CV(estimate) ≈ 30% (4 papers) / ≈ 10%, totals ≈ 32% � USA • ANR = B12/day required to just restore normal haematological status in PA patients = 1.40 (3 out of 7 normalized) • “median” of 7 data points, very imprecise, CV = ?? � Conclusion • Liver size, bile loss, IF-binding considered fixed (“known”) • Between-study variation is usually large (ignored) • Formula’s not consistent (Fr, NL) • Errors are lower limits: total error in estimate ANR is large!

Search strategy Eurreca NoE (example vit B12) � “Wide” (sensitive) search • vitamin B 12 , “biomarkers”, “health outcomes” • Aimed at associations “intake” – “status” – “health” (I-S-H) � Selection process • 5913 papers, screened for in/exclusion criteria • 903 full text papers screened for in/exclusion • 84 full text papers screened for I-S, I-H, S-H dose response data � Results • I/S-H: Cognition (19), Osteoporosis (10), Neurologic disease (7), Anemia (2) • I-S: 28 RCT, 21 observational studies (37 and 20 estimates)

Extended evidence base, incl. RCT & X-sectional Method Refs, yr N total , sex Pop, remarks Conclusions Healthy subjects daily loss of total Whole body 6 13 body pool = 0.15% counting 1960-68 male (SE=0.01%) healthy, cholecyst- biliary loss roughly Bile losses 6 38 ectomised, post- estimated as 1.4 1956-91 mixed, not operative, with(hout) ug/day specified pernicious anaemia pernicious anaemia At 1.4 ug/day 4/7 Maintenance 1 7 patients subjects reached a haematological 1958 sex not normal haemato- status specified logical status ≈ 75 Healthy subjects. BF = 50% Bioavailability 11 Foods raw/cooked, range 5-65% 1959-01 mixed, most high/low B12 content High dose: less unspecified 24 multivit capsules ? RCTs serum/ 37 3398 13 diet / enriched food Until now, not used plasma B12 conc. (21-217) dose 2.1 – 1000ug 17 X-sectional, 17 ? X-section serum/ 20 12,570 baseline from cohort Until now, not used plasma conc. (64-2999)