Use of penalized splines in extended Cox-type additive hazard regression to flexibly estimate the effect of time-varying serum uric acid on risk of cancer incidence: a prospective, population-based study in 78,850 men.
OBJECTIVE
We sought to investigate the effect of serum uric acid (SUA) levels on risk of cancer incidence in men and to flexibly determine the shape of this association by using a novel analytical approach.


METHODS
A population-based cohort of 78,850 Austrian men who received 264,347 serial SUA measurements was prospectively followed-up for a median of 12.4 years. Data were collected between 1985 and 2003. Penalized splines (P-splines) in extended Cox-type additive hazard regression were used to flexibly model the association between SUA, as a time-dependent covariate, and risk of overall and site-specific cancer incidence and to calculate adjusted hazard ratios with their 95% confidence intervals.


RESULTS
During follow-up 5189 incident cancers were observed. Restricted maximum-likelihood optimizing P-spline models revealed a moderately J-shaped effect of SUA on risk of overall cancer incidence, with statistically significantly increased hazard ratios in the upper third of the SUA distribution. Increased SUA (>/=8.00 mg/dL) further significantly increased risk for several site-specific malignancies, with P-spline analyses providing detailed insight about the shape of the association with these outcomes.


CONCLUSIONS
Our study is the first to demonstrate a dose-response association between SUA and cancer incidence in men, simultaneously reporting on the usefulness of a novel methodological framework in epidemiologic research.
Strasak
Alexander M
AM
Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Austria. alexander.strasak@i-med.ac.at
Lang
Stefan
S
Kneib
Thomas
T
Brant
Larry J
LJ
Klenk
Jochen
J
Hilbe
Wolfgang
W
Oberaigner
Willi
W
Ruttmann
Elfriede
E
Kaltenbach
Lalit
L
Concin
Hans
H
Diem
Günter
G
Pfeiffer
Karl P
KP
Ulmer
Hanno
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000453:epidemiology*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013997:Time Factors; D014527:Uric Acid / Q000097:blood*; D055815:Young Adult
D015415:Biomarkers; D014527:Uric Acid