title: Hemoglobin variability and mortality: confounding by disease severity.
abstract: BACKGROUND
  Substantial variability in hemoglobin levels has been associated with increased mortality risk in hemodialysis patients. Variability also has been associated with concurrent comorbid conditions and hospitalization. Adequate adjustment for confounding by disease severity is needed to estimate the association of hemoglobin level variability with mortality risk.
  
  
  METHODS
  Retrospective cohort study.
  
  
  METHODS
  Medicare hemodialysis patients in 3 groups: prevalent on July 1, 2006 (n = 133,246), prevalent on July 1, 1996 (n = 78,602), and incident between January 1, 2005, and June 30, 2006 (n = 24,999).
  
  
  METHODS
  Hemoglobin level variability estimated using the residual deviation around the linear trend in hemoglobin levels during a 6-month entry period.
  
  
  RESULTS
  Time to death.
  
  
  METHODS
  We fit Cox models of 1-year mortality with and without adjustment for disease severity (comorbid conditions, hospitalization days, and months with hemoglobin level <10 g/dL), measured concurrently with hemoglobin level variability.
  
  
  RESULTS
  Disease severity was associated positively with hemoglobin level variability in all groups. Before adjustment for disease severity, HRs for hemoglobin level variability were 1.27 (95% CI, 1.24-1.31) per 1 g/dL for patients prevalent in 2006, 1.32 (95% CI, 1.27-1.38) for patients prevalent in 1996, and 1.08 (95% CI, 1.03-1.13) for patients incident in 2005-2006. After adjustment, HRs for hemoglobin level variability were 1.02 (95% CI, 0.99-1.05), 1.07 (95% CI, 1.03-1.12), and 1.01 (95% CI, 0.95-1.06), respectively.
  
  
  CONCLUSIONS
  We did not adjust for time-varying confounding of hemoglobin level; an inclusion requirement introduces potential selection bias; our findings may not apply to incident hemodialysis patients younger than 65 years; assessment of comorbid conditions from claims is subject to misclassification, with possible residual confounding attributable to comorbid conditions; this observational study cannot prove causality.
  
  
  CONCLUSIONS
  After adjustment for concurrent disease severity, evidence supporting an association between hemoglobin level variability and mortality risk was weak and inconsistent. The clinical utility of hemoglobin level variability may be limited.
authors.affiliation: Minneapolis Medical Research Foundation, MN, USA. eweinhandl@cdrg.org
authors.forename: Eric D
authors.initials: ED
authors.lastname: Weinhandl
authors.forename: Yi
authors.initials: Y
authors.lastname: Peng
authors.forename: David T
authors.initials: DT
authors.lastname: Gilbertson
authors.forename: Brian D
authors.initials: BD
authors.lastname: Bradbury
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Collins
mesh_terms: D000328:Adult; D000368:Aged; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000097:blood* / Q000401:mortality* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D006435:Renal Dialysis; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015996:Survival Rate
chemical_list: D006454:Hemoglobins