Fylgni og orsakasamband: Dæmi um áhorfs- og íhlutandi rannsóknir sem hafa gefið

misvísandi niðurstöður varðandi orsakasamband

Þórhallur Ingi Halldórsson, dósentMatvæla- og Næringafræðideild HÍ

Lækn

adag

ar20

14Faralds- og líftölfræði fyrir klíníska lækna – vinnubuðir

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

Cohort RCT

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

- 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

- 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

- 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.

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

Sambærilegar niðurstöður

Af hverju

Skekkjur við mat á neyslu

EN hvaðan kemur beta carotene

eða

?

• 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

Grænmeti og ávextir

the time has come to seriously ask whether antioxidantuse much more likely causes than prevents cancer

Blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.

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“.

• Su tilgáta er prófuð með miklum tilkostnaði í vel hannaðri RCT

• Niðurstöður standa ekki undir væntingum

RÍN við HÍ og LSH

Hvaðan kemur fólat- ýmsir fæðuflokkar, (danskar niðurstöður n=900) -

Variable Mean (mg/day) Std Dev ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ folat_total 425.7 131.0 folat_milk 42.8 29.7 folat_Cereals 79.6 39.6 folat_Vegetables 156.2 74.9 folat_Fruits 51.0 36.3 folat_Red_meat 49.8 33.3 folat_Fish 8.8 5.6 folat_Poultry 7.6 5.0 folat_Eggs 5.6 3.9 folat_Fats 1.2 0.9 folat_Sweets 0.9 1.0 folat_beverages 11.8 15.1 ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ

X2, >100 !!

X15-25

Skýringar• Ef tengsl finnast fyrir lífstílsbreytur eins og ….

– Hreyfingu– (Tóbak, Áfengi)– Matvæli– eða klínísk mæligildi í blóði (D-vítamín, CRP, homocystein…)

• Þá er allt í lagi að staldra við og velta vandlega fyrir sér lífeðlisfræðilegum mekansima

• 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

Viðhorf til Faraldsfræði

• Mun líklegra að ….– viðhorf rannsakanda– vankunnátta m.t.t líftölfræði– 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

Dæmi 3Oft auðveldara að sýna fram á svipuð tengls í fáhorfsrannsóknum og hafa

fengist í RCT-rannsóknum

• RCT-rannsókn fer urskeiðis

• Ekki siðferðislega verjandi að endurtaka rannsókn

• Notast við áhorfsrannsóknir til að athuga hvort hægt sé að staðfesta tengsl/áhrif

Background – The Harlem Trail

• A RCT trial of nutritional supplementation conducted in 1976 in New York City

• Poor black urban population

• 1051 pregnant black women enrolled prior to week 30

• 770 completed the trail

The Harlem Trail• Aim of study was to increase birth weight and influence the postnatal

development of the offspring of mothers at high risk of having low birth weight infants

• 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

The Harlem Trail• Aim of study was to increase birth weight and influence the postnatal

development of the offspring of mothers at high risk of having low birth weight infants

• 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

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

The trail produced unexpected results

• Balanced protein supplementation– the proportion of low birth weight was reduced, – non-significant increase in birth weight (41g)– and length of gestation was increased.

• High protein 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

The trail produced unexpected results

• Balanced protein supplementation– the proportion of low birth weight was reduced, – non-significant increase in birth weight (41g)– and length of gestation was increased.

• High protein 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

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