Læknadagar2014
Faralds- og líftölfræði fyrir klíníska lækna – vinnubúðir
Fylgni og orsakasamband: Dæmi um áhorfs- og íhlutandi
rannsóknir sem hafa gefið
misvísandi niðurstöður varðandi orsakasamband
Þórhallur Ingi Halldórsson, dósent
Matvæla- og Næringafræðideild HÍ
Áhorfsrannsóknir og íhlutandi (RCT)
Af hverju ber þeim oft ekki saman
Cohort
RCT
Dæmi 1
Röng 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 alphatocopherol, 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: alphatocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alphatocopherol 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 alphatocopherol, 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: alphatocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alphatocopherol 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 alphatocopherol, 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: alphatocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alphatocopherol 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
?
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
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.
Dæmi 2
Áhorfsrannsóknir 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
Hvaðan kemur fólat
- ýmsir fæðuflokkar, (danskar niðurstöður n=900) -
Mean (mg/day) Std Dev
Variable
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
131.0
425.7
folat_total
29.7
42.8
folat_milk
39.6
79.6
folat_Cereals
74.9
156.2
folat_Vegetables
36.3
51.0
folat_Fruits
33.3
49.8
folat_Red_meat
5.6
8.8
folat_Fish
5.0
7.6
folat_Poultry
3.9
5.6
folat_Eggs
0.9
1.2
folat_Fats
1.0
0.9
folat_Sweets
15.1
11.8
folat_beverages
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
RÍN við HÍ og LSH
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 3
Oft 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
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 ??