American Journal of Kidney Diseases
Volume 54, Issue 3 , Pages 554-560 , September 2009

Evolving Statistical Methods to Facilitate Evaluation of the Causal Association Between Erythropoiesis-Stimulating Agent Dose and Mortality in Nonexperimental Research: Strengths and Limitations

  • Brian D. Bradbury, MA, DSc

      Affiliations

    • Department of Biostatistics and Epidemiology, Amgen Inc, Thousand Oaks, CA
    • Corresponding Author InformationAddress correspondence to Brian D. Bradbury, MA, DSc, Department of Biostatistics & Epidemiology, Amgen Inc, One Amgen Center Dr, MS: 24-2-A, Thousands Oaks, CA 91320
  • ,
  • M. Alan Brookhart, PhD

      Affiliations

    • Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA
  • ,
  • Wolfgang C. Winkelmayer, MD, ScD, MPH

      Affiliations

    • Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA
    • Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA
  • ,
  • Cathy W. Critchlow, PhD

      Affiliations

    • Department of Biostatistics and Epidemiology, Amgen Inc, Thousand Oaks, CA
  • ,
  • Ryan D. Kilpatrick, PhD

      Affiliations

    • Department of Biostatistics and Epidemiology, Amgen Inc, Thousand Oaks, CA
  • ,
  • Marshall M. Joffe, MD, PhD, MPH

      Affiliations

    • Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA
  • ,
  • Harold I. Feldman, MD, MSCE

      Affiliations

    • Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA
    • Department of Medicine, University of Pennsylvania, Philadelphia, PA
  • ,
  • John F. Acquavella, PhD

      Affiliations

    • Department of Biostatistics and Epidemiology, Amgen Inc, Thousand Oaks, CA
  • ,
  • Ouhong Wang, PhD

      Affiliations

    • Department of Biostatistics and Epidemiology, Amgen Inc, Thousand Oaks, CA
  • ,
  • Kenneth J. Rothman, DrPH

      Affiliations

    • Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA
    • RTI Health Solutions, Research Triangle Park, NC

Received 19 December 2008 ,Accepted 6 May 2009.

References 

  1. Besarab A, Boton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584–590
  2. Drueke TB, Locatelli F, Clyne N, et al. CREATE Investigators Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–2084
  3. Singh AK, Szczech L, Tang KL, et al. CHOIR Investigators Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–2098
  4. US Renal Data System. USRDS 2004 Annual Data Report. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2005;
  5. Miettinen OS, Cook EF. Confounding: Essence and detection. Am J Epidemiol. 1981;114:593–603
  6. Greenland S, Neutra R. Control of confounding in the assessment of medical technology. Int J Epidemiol. 1980;9:361–367
  7. Joffe MM. Confounding by indication: The case of calcium channel blockers. Pharmacoepidemiol Drug Safety. 2000;9:37–41
  8. Rossert J, Gassmann-Mayer C, Frei D, McClellan W. Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients. Nephrol Dial Transplant. 2007;22:794–800
  9. Roberts TL, Obrador GT, St Peter WL, Pereira BJ, Collins AJ. Relationship among catheter insertions, vascular access infections and anemia management in hemodialysis patients. Kidney Int. 2004;66:2429–2436
  10. Ebben JP, Gilbertson DG, Foley RN, Collins AJ. Hemoglobin level variability: Associations with comorbidity, intercurrent events and hospitalizations. Clin J Am Soc Nephrol. 2006;1:1205–1210
  11. Cooper BA, Penne EL, Bartlett LH, Pollock CA. Protein malnutrition and hypoalbuminuria as predictors of vascular events and mortality in ESRD. Am J Kidney Dis. 2004;43:61–66
  12. Bradbury BD, Critchlow CW, Weir M, Stewart R, Krishnan MK, Hakim R. Impact of elevated C-reactive protein levels on erythropoiesis stimulating agent dose and responsiveness. Nephrol Dial Transplant. 2009;24:919–925
  13. Honda H, Qureshi AR, Heimburger O, et al. Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis. 2006;47:139–148
  14. Astor BC, Eustace JA, Powe NR, Klag MJ, Fink NE, Coresh J. Type of vascular access and survival among incident hemodialysis patients: The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study. J Am Soc Nephrol. 2005;16:1449–1455
  15. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in HD patients. J Am Soc Nephrol. 1999;10:610–619
  16. Kausz AT, Solid C, Pereira BJ, Collins AJ, St Peter WL. Intractable anemia among hemodialysis patients: A sign of suboptimal management or a marker of disease?. Am J Kidney Dis. 2005;45:136–147
  17. Gilbertson DT, Ebben JP, Foley RN, Weinhandl ED, Bradbury BD, Collins AJ. Hemoglobin level variability: Associations with mortality. Clin J Am Soc Nephrol. 2008;3:133–138
  18. Rothman KJ, Wentworth CE. Mortality of cystic fibrosis patients treated with tobramycin solution for inhalation. Epidemiology. 2003;14:55–59
  19. Weiss NS, Dublin S. Accounting for time-dependent covariates whose levels are influenced by exposure status. Epidemiology. 1998;9:436–440
  20. Kapoian T, O'Mara NB, Singh AK, et al. Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J Am Soc Nephrol. 2008;19:372–379
  21. Ibrahim H, Foley RN, Zhang R, Gilbertson DT, Collins AJ. Parenteral iron use: Possible contribution to exceeding target hemoglobin in hemodialysis patients. Clin J Am Soc Nephrol. 2009;4:623–629
  22. Bradbury BD, Danese M, Gleeson M, Critchlow CW. Effect of epoetin alfa dose changes on hemoglobin and mortality in hemodialysis patients with hemoglobin levels persistently below 11 g/dL. Clin J Am Soc Nephrol. 2009;4:630–637
  23. Solid C, Foley RN, Gilbertson DT, Collins AJ. Perihospitalization epoetin-hematocrit associations in US hemodialysis patients, 1998 to 2003. Hemodial Int. 2007;11:442–447
  24. Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research. Epidemiology. 1999;10:37–48
  25. Bradbury BD, Wang O, Critchlow CW, et al. Exploring relative mortality and epoetin alfa among hemodialysis patients. Am J Kidney Dis. 2008;51:62–70
  26. Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11:550–560
  27. Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology. 2000;11:561–570
  28. van der Laan MJ, Peterson ML, Joffe MM. History adjusted marginal structural models and statically-optimal dynamic treatment regimens. Int J Biostat. 2005;1:1–41
  29. Robins JM, Hernan M, Rotnitzky A. Effect modification by time-varying covariates. Am J Epidemiol. 2007;166:994–1002
  30. Petersen ML, van der Laan MJ. Respond to “Effect modification by time-varying covariates.”. Am J Epidemiol. 2007;166:1003–1004
  31. Brookhart MA, Wang PS, Solomon DH, Schneeweiss S. Evaluating short-term drug effects using a physician-specific prescribing preference as an instrumental variable. Epidemiology. 2006;17:1–8
  32. Wen SW, Kramer MS. Uses of ecologic studies in the assessment of intended treatment effects. J Clin Epidemiol. 1999;52:7–12
  33. Brooks JM, Chrischilles EA, Scott SD, Chen-Hardee SS. Was breast conserving surgery underutilized for early stage breast cancer? (Instrumental variables evidence for stage II patients from Iowa). [erratum in Health Serv Res 39:693, 2004] Health Serv Res. 2003;38:1385–1402
  34. Johnston SC. Combining ecological and individual variables to reduce confounding by indications: Case study—Subarachnoid hemorrhage treatment. J Clin Epidemiol. 2000;53:1236–1241
  35. Brooks JM, Irwin CP, Hunsicker LG, Flanigan MJ, Chrischilles EA, Pendergast JF. Effect of dialysis center profit status on patient survival: A comparison of risk adjustment and instrumental variable approaches. Health Serv Res. 2006;41:2267–2289
  36. Collins AJ, Ebben BS, Gilbertson DT. ESA adjustments in patients with elevated hemoglobin levels: Provider practice patterns compared with recommended practice guidelines. Am J Kidney Dis. 2006;49:135–142
  37. Harris KM, Remler DK. Who is the marginal patient? (Understanding instrumental variables estimates of treatment effects). Health Serv Res. 1998;33:1337–1360
  38. Brookhart MA, Schneweiss S. Preference-based instrumental variable methods for estimation of treatment effects: Assessing validity and interpreting results. Int J Biostat. 2007;3:1–23
  39. Robins JM. Correcting for non-compliance in randomized trials using structural nested mean models. Comm Stat. 1994;23:2379–2412
  40. Robins JM. Analytic methods for estimating HIV treatment and cofactor effects. In:  Ostrow G,  Kessler R editor. Methodological Issues of AIDS Mental Health Research. NY, NewYork: Plenum; 1993;p. 213–290

 Originally published online as doi: 10.1053/j.ajkd.2009.05.010 on July 10, 2009.

 Because an author of this manuscript is an editor for AJKD, the peer-review and decision-making processes were handled entirely by an Associate Editor (Adeera Levin, MD, University of British Columbia) who served as Acting Editor-in-Chief. Details of the journal's procedures for potential editor conflicts are given in the Editorial Policies section of the AJKD website.

PII: S0272-6386(09)00833-6

doi: 10.1053/j.ajkd.2009.05.010

American Journal of Kidney Diseases
Volume 54, Issue 3 , Pages 554-560 , September 2009