Evidence for health effects of what we eat: how to integrate findings from intervention and observational studies?

Transcription

1 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

2 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 ( ): micronutrients

3 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, INL97.5 (Recommended Dietary Intake) 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. Biological variation: susceptibility *source: FNB:IOMFood and Nutrition Board: Institute of Medicine DRI process King et al. 2007

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

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

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

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

8 Balance approach ( in = out ): example vit. B12 ANR Sum of losses (faeces, urine, skin,., periods) + need for growth (fetus, child, pregnancy, lactation,..) Bioavailability Factor Health criterion Netherlands: Maintenance liver stores B12 > 500 µg 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

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

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

11 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))

12 Cross-tab pyramid by data for requirements Methodology (Gibney) Depletion-repletion + (no random alloc) Prosp. cohort Radio-active tracers + Intervention Casecontrol Crosssection Ecological Balance studies + Factorial methods + Tissue levels + Biochemical markers + () + Biological markers + () + Animal experiments + () Red: Mainly used in setting reference values (data limited) Box: Seldomly used (plenty of data available) OPPORTUNITY!! NB: Nutritional status subjects in <represent. than X-sectional

13 Study methods by concept and design Study concept Balance i.e. input = output (under steady state condition) Example B12 Dose-response between intake and outcome (after reaching steady state condition) Examples B12 Intervention design (manipulates the exposure) Depletion-repletion (quasi experimental) Maintenance haematological status in pernicious anaemia patients (stable Hb, normal MCV & normal reticulocyte response) (US), using supplements, enriched foods, whole diets Independent approaches Same results (ANRs)? ervational design (assesses the exposure) Radioactive tracers (whole body count) Factorial methods (faeces, skin, etc) Tissue levels (liver) Biliary stores > 500ug (NL) Biliary losses (FR) Cross-sectional studies, intake by dietary assessment Same markers, different designs: How to integrate? Relation to serum/plasma vitb12 levels, methylmalonic acid (MMA), serum/plasma holo-transcobalamin (holotc)

14 Evidence base balance approach (B12) Method Refs, yr Ntotal, sex Pop, remarks Conclusions Whole body counting male Healthy subjects daily loss of total body pool = 0.15% (SE=0.01%) Bile losses mixed, not specified healthy, cholecystectomised, postoperative, with(hout) pernicious anaemia biliary loss roughly estimated as 1.4 ug/day Maintenance haematological status sex not specified pernicious anaemia patients At 1.4 ug/day 4/7 subjects reached a normal haematological status Bioavailability mixed, most unspecified Healthy subjects. Foods raw/cooked, high/low B12 content BF = 50% range 5-65% High dose: less

15 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!

16 Search strategy Eurreca NoE (example vit B12) Wide (sensitive) search vitamin B12, 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, 21 observational studies (37 and 20 estimates)

17 Extended evidence base, incl. & X-sectional Method Refs, yr Ntotal, sex Pop, remarks Conclusions Whole body counting male Healthy subjects daily loss of total body pool = 0.15% (SE=0.01%) Bile losses mixed, not specified healthy, cholecystectomised, postoperative, with(hout) pernicious anaemia biliary loss roughly estimated as 1.4 ug/day Maintenance haematological status sex not specified pernicious anaemia patients At 1.4 ug/day 4/7 subjects reached a normal haematological status Bioavailability mixed, most unspecified Healthy subjects. Foods raw/cooked, high/low B12 content BF = 50% range 5-65% High dose: less s serum/ plasma B12 conc (21-217) 24 multivit capsules 13 diet / enriched food dose ug? Until now, not used X-section serum/ plasma conc ,570 ( ) 17 X-sectional, 17 baseline from cohort? Until now, not used

18 Study means of observational studies Means of status and intake in all studies Intake: 7 ug/day Status 300 ug/l Much more interesting: associations, i.e. regression coeff. (or r), if available

19 Effect size: Forest plots s and observational Study Year Design Beta (95% CI) Al-Khatib et al (-0.02, 0.05) Bates et al (-0.01, 0.07) Campbell et al (0.01, 0.09) Garry et al (0.24, 0.33) Hoey et al (0.00, 0.00) Crosssectional Nath et al. Planells et al. Shuaibi et al. Tucker et al. Van Asselt et al. Van Guelpen et al. Vogiatzoglou et al (I) Vogiatzoglou et al. (II) (0.02, 0.17) 0.09 (0.04, 0.13) 0.19 (0.03, 0.34) 0.21 (0.19, 0.23) 0.54 (0.27, 0.81) (-0.11, 0.09) 0.12 (0.08, 0.15) 0.08 (0.05, 0.11) Vogiatzoglou et al. (III) (0.03, 0.12) Vogiatzoglou et al. (IV) (0.09, 0.20) Waldmann et al (-0.07, 0.07) Weinstein et al (0.04, 0.25) Woods et al (-0.06, 0.06) Yang et al (-0.11, 0.12) Appel et al (-0.16, 1.96) Church et al (0.06, 0.13) Clarke et al (0.13, 0.17) Cockle et al. (m) (-0.04, 0.16) Cockle et al. (f) (0.14, 0.33) De Jong et al. (enr. foods + exerc) (0.88, 2.28) De Jonget al (enr. foods) (0.53, 1.10) Dhonukshe-Rutten et al. (milk) (0.11, 0.19) Dhonukshe-Rutten et al. (caps) (0.11, 0.19) Earnest et al (0.09, 0.12) Eussen et al. (vitb12 caps) (0.17, 0.22) Eussen et al. (multivit caps) (0.21, 0.25) Flicker et al (0.15, 0.19) Green et al (0.14, 0.20) Grieger et al (0.22, 0.43) Lewerin et al (0.09, 0.14) Manders et al (-0.01, 0.60) McKay et al (0.54, 1.18) McMahon et al (0.13, 0.16) Seal et al. (low) Seal et al. (high) Spiller et al. Tapola et al. Telford et al. Tobin et al (0.05, 0.29) 0.21 (0.15, 0.26) 0.06 (0.01, 0.11) 0.03 (-0.11, 0.18) 0.18 (0.12, 0.24) 0.12 (0.07, 0.17) Tucker et al (0.21, 0.61) Ubbink et al. (vitb12 caps) (0.06, 0.19) Ubbink et al. (multivit caps) Van Vliet et al. (m, spread 1) Van Vliet et al. (f, spread 1) Van Vliet et al. (m, spread 2) (0.09, 0.19) (-0.41, 0.40) 0.31 (-0.17, 0.78) 0.07 (-0.33, 0.48) Van Vliet et al. (f, spread 2) (0.10, 0.93) Weight et al (-0.04, 0.05) Winkels et al (0.31, 0.51) Wolters et al (0.19, 0.35) Wouters-Wesseling et al (0.48, 1.33) Yajnik et al (0.06, 0.20) Overall (I-squared = 98.3%, p = 0.000) 0.16 (0.12, 0.19) NOTE: Weights are from random effects analysis

20 Dose response meta-analysis B12 ( intake-status ) Crosssectional s & X- sectional combined

21 Preliminary regression slopes (stratified analysis) Pooled β overall (95%CI) Pooled β adults 1 (95%CI) Pooled β elderly 2 (95%CI) s 0.17 ( ) 0.14 ( ) 0.19 ( ) ervational 0.09 ( ) 0.08 ( ) 0.13 ( ) Combined 0.16 ( ) 0.11 ( ) 0.18 ( ) Regression line log e (conc) = *log e (intake) All association (slopes) highly significant Intake 4 to 11 ug serum/plasma conc 253 to 297 pmol/l(i.e. +16%) Stratified analysis ervational weaker than s; combined close to Suggests tronger association in elderly

22 Dose response meta-analysis B12 ( intake-status ) Crosssectional s Trad ANR±20% & X- sectional combined Traditional ANR >> projected ANR based on regression line

23 How to derive pop ref intakes using and observational data? Extended meta-analysis for Intake-Status Traditional meta-analysis: focus on one parameter (e.g. beta Intake-Status, deterministic ) Extended meta-analysis: estimate the bivariate distribution in a target population ( stochastic ) Intake-status relation (β SI or ρ SI ) Intake distribution (µ I, σ I ) Status distribution (µ S, σ S ) These 5 define the bivariate distribution I-S status intake

24 Correlations instead of slopes (95 % conf ellipses) Heterogeneous results for r (or B,Sx,Sy) represented by ellipses (as for individuals!) meta-analysed r = 0.38 (correlation of ln(intake) with ln( status )

25 ervational data (o) and data (+) Extended meta-analysis r=0.29 b yx = 0.16 b xy -1 = 0.16 / = 1.90 In a scenario with increased intake, which line to follow? Method 2: Predict status intake (public health scenarios) Method 1: Predict required intake clinical health endpoint

26 Extrapolation method 2: status intake Projected optimal scenario Health criterion (physiological requirement) Projected requirement distribution data 5.2% This mean intake is sufficient for 97.5% of subjects INL2.5...ANR...INL97.5

27 Extrapolation method 2: status intake If we extrapolate to sufficient status for 97% of people Prevalence reduces but mean intake has to increase to ca 10 ug Extrapolation is in the range of observational and data If we extrapolate the line to prevalence insufficiency =50% this projected ANR is much less than the current ANR Although the observed CV is very large, the projected RDA will probably be >>> 20% above the projected ANR Note: this extrapolation is outside the range of observed data, it is very much to the extreme lower end of the observations (and this with large imprecision)

28 Extrapolation meth. 1 (intake borderline status) Corresponds to question: What intake is required to just prevent the adverse health outcome in 50% of the people: Given marginal health, what is the corresponding intake of that population? Unlike extrapolation method 2, this method would lead to an ANR and RDA above the current values Intake vitb12 (log scale)

29 Comparison balance and dose response Balance based on very limited data (24 studies, > 100 subj), close to clinical endpoint high imprecision of estimate, CVbetween persons of 10% pragmatic. evaluation of intake beyond range of observations Dose response > 2 x the # of studies (57), and 100 x the # subjects (>15,000), healthy people projected ANR (RDA) could be lower or higher, depending on model assumptions evaluation of intake: predict prev. of inadequacy (in range of observ.) need to reconsider the concept intake status (clinical) or status intake (PH) and health criteria??

30 Further work / work in progress Statistical model: Refine estimates, try to reduce between-study variation, understanding the extrapolation methods, individual data! Apply to Eurreca databases: folate, iodine (if possible iron, zinc). Regarding the size of evidence base similar results anticipated. Findings on ANRs and scenario s generalizable to other micronut s? Discuss health criterion (150ug/L serum/plasma), more clinically relevant endpoints (add cognition, osteoporosis, neurologic disease, to pernicious anemia & liver stores). What is nutritional health? Extend model I-S to I/S-H (trivariate), but so far lack of sufficient data on hard health endpoints (disease risk, suboptimal function). Here imprecision is a big issue, as with the traditional approach. Discuss methodol. and prelim results in scientific meetings (here & now) and with recommendation setting bodies (workshop < mid 12)

31 Thanks for your attention 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, Pieter van t Veer and all other co-workers in the EURRECA NoE