History-adjusted marginal structural analysis of the association between hemoglobin variability and mortality among chronic hemodialysis patients.
OBJECTIVE
Hemoglobin variability is common among dialysis patients, and has been associated with increased mortality. The causal nature of this association has been difficult to ascertain because of potential time-dependent confounding, for which traditional statistical methods do not control.


METHODS
A retrospective cohort of 34,963 Fresenius Medical care dialysis patients from 1996 was assembled. Hemoglobin variability, absolute hemoglobin level, and temporal hemoglobin trend were measured over rolling 6-mo exposure windows. Their association with mortality was estimated using history-adjusted marginal structural analysis that adjusts for time-dependent confounding by applying weights to observations inversely related to the predictability of observed levels of hemoglobin.


RESULTS
In the primary analysis, each g/dl increase in hemoglobin variability was associated with an adjusted hazard ratio (HR) [95% confidence interval (CI)] for all-cause mortality of 1.93 (1.20 to 3.10). Neither higher absolute hemoglobin level nor increasing hemoglobin trend were significantly associated with mortality; adjusted HR (95% CI) 0.85 (0.64 to 1.11) and 0.60 (0.25 to 1.45), respectively.


CONCLUSIONS
Marginal structural analysis demonstrates that hemoglobin variability is associated with increased mortality among chronic hemodialysis patients, and that this effect is more pronounced than appreciated using standard statistical techniques that do not take time-dependent confounding into account.
Brunelli
Steven M
SM
Renal, Electrolyte and Hypertension Division of the Department of Medicine, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Joffe
Marshall M
MM
Israni
Rubeen K
RK
Yang
Wei
W
Fishbane
Steven
S
Berns
Jeffrey S
JS
Feldman
Harold I
HI
D000368:Aged; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D015986:Confounding Factors, Epidemiologic; D003627:Data Interpretation, Statistical; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D006435:Renal Dialysis / Q000401:mortality*; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
D015415:Biomarkers; D006454:Hemoglobins