Þórhallur Ingi Halldórsson , dósent Matvæla - og Næringafræðideild HÍ

1. Faralds- oglíftölfræðifyrirklínískalækna – vinnubúðir Fylgni og orsakasamband: Dæmi um áhorfs- og íhlutandirannsóknirsemhafagefiðmisvísandiniðurstöðurvarðandiorsakasamband Læknadagar2014 ÞórhallurIngiHalldórsson, dósent Matvæla- ogNæringafræðideild HÍ

2. Áhorfsrannsóknir og íhlutandi (RCT)Af hverju ber þeim oft ekki saman RCT Cohort

3. Dæmi 1Röng túlkun áhorfsrannsókna (observational studies) • Áhugaverð tengsl finnast ítrekað í áhorfsrannsóknum og sett fram fremur langsótt tilgáta. • Tilgáta er prófuð með miklum tilkostnaði í vel hannaðri RCT (Randomized Clinical Trial) • Niðurstöður standa ekki undir væntingum

8. - The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. - • BACKGROUND. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. • METHODS. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. • CONCLUSIONS. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects. • Ath 100g af gulrætum gefa ca 12mg beta carotene

9. - The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. - • BACKGROUND. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. • METHODS. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. • CONCLUSIONS. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects. • Gáfu 20mg beta carotene • 100g af gulrætum gefa ca 12mg beta carotene

10. - The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. - • BACKGROUND. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. • METHODS. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. • CONCLUSIONS. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.

12. 1193 cases (beta ca.) versus 1098 cases (placebo) (ITT: ↑8.6%)

13. Sambærilegar niðurstöður

14. Af hverju

18. Skekkjurvið mat á neyslu

20. EN hvaðan kemur beta carotene

21. eða ?

22. Grænmeti og ávextir • Verndandi áhrif grænmetis og ávaxta ekki bara vegna andoxunarefna: • trefjar • B-vítamín (fólínsýra) • Induction of detoxification enzymes • Modulation of the immune system • Reduction of platelet aggregation • Reduction of cholesterol synthesiss • Modulation of hormone metabolismsm • Reduction of blood pressure • Antibacterial effects • Antiviral effects

23. the time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer Blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.

25. Dæmi 2Áhorfsrannsóknir eru ekki eins rang-túlkaðar en tengslin eru ekki „causal“ • Áhugaverð en mun sértækari tengsl finnast ítrekað í áhorfsrannsóknum og sett fram tilgáta sem lífeðlisfræðilega „heldur vatni“. • Sú tilgáta er prófuð með miklum tilkostnaði í vel hannaðri RCT • Niðurstöður standa ekki undir væntingum

28. Hvaðan kemur fólat- ýmsir fæðuflokkar, (danskar niðurstöður n=900) - RÍN við HÍ og LSH

31. X2, >100 !! X15-25

38. Skýringar • Ef tengsl finnast fyrir lífstílsbreytureins og …. • Hreyfingu • (Tóbak, Áfengi) • Matvæli • eðaklínískmæligildi í blóði (D-vítamín, CRP, homocystein…) • Þá er allt í lagi að staldra við og velta vandlega fyrir sér lífeðlisfræðilegummekansima • Gera minni tilraunir til að skilja hvaða þættir hafa áhrif á mælinguna okkar og hvernig mæligildið hagar sér • … áður en lagt er af stað með dýrar RCT-tilraunir sem geta endað með ósköpun

39. Viðhorf til Faraldsfræði • Mun líklegra að …. • viðhorf rannsakanda • vankunnátta m.t.tlíftölfræði • áhugaleysi á að kalla til og vinna með sérfræðingum sem þekkja betur til ákveðinna þátta ransóknar … leiði til rangrar niðurstöðu EN að faraldsfræði sé svo ónákvæm að ekkert mark sé á henni takandi

40. Dæmi 3Oft auðveldara að sýna fram á svipuð tengls í fáhorfsrannsóknum og hafa fengist í RCT-rannsóknum • RCT-rannsókn fer úrskeiðis • Ekki siðferðislega verjandi að endurtaka rannsókn • Notast við áhorfsrannsóknir til að athuga hvort hægt sé að staðfesta tengsl/áhrif

41. Background – TheHarlemTrail • A RCT trial of nutritional supplementation conducted in 1976 in New York City • Poorblackurbanpopulation • 1051 pregnantblackwomenenrolledpriortoweek 30 • 770 completedthetrail

42. TheHarlemTrail • Aim of studywastoincreasebirthweight and influencethepostnataldevelopment of the offspring of mothers at highrisk of havinglowbirthweightinfants • It was a 3-arm beverage supplemental trail: • Controls: received no protein supplementation • Complimental group: received balanced protein supplementation (6g/day casein) • Supplemental group: received high protein supplementation (40g day casein) • All three groups all received micronutrient supplementation

43. TheHarlemTrail • Aim of studywastoincreasebirthweight and influencethepostnataldevelopment of the offspring of mothers at highrisk of havinglowbirthweightinfants • 3-arm beverage supplemental trail: • Controls: received no protein supplementation • Complimental group: received balanced protein supplementation (6g/day casein) • Supplemental group: received high protein supplementation (40g day casein) • All three groups all received micronutrient supplementation

44. In the high protein group dietary and supplemental protein combined was around 20% of total energy intake.

45. Thetrailproducedunexpected results • Balancedproteinsupplementation • theproportion of lowbirthweightwasreduced, • non-significantincrease in birthweight (41g) • and length of gestationwasincreased. • Highprotein supplementation resulted in • excess of early preterm births and associated neonatal deaths • Significant growth retardation up to week 37 of gestation • These adverse effcts were borderline (not formally) significant

46. Thetrailproducedunexpected results • Balancedproteinsupplementation • theproportion of lowbirthweightwasreduced, • non-significantincrease in birthweight (41g) • and length of gestationwasincreased. • Highprotein supplementation resulted in • excess of early preterm births and associated neonatal deaths • Significant growth retardation up to week 37 of gestation • These adverse effcts were borderline (not formally) significant

48. Hvað þurfum við að taka inn mikið af D-vítamíni ??