International Journal of Clinical Oncology

, Volume 14, Issue 2, pp 102–111 | Cite as

Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials

Review Article

Abstract

The identification and validation of putative surrogate endpoints in oncology is a great challenge to medical investigators, statisticians, and regulators. A putative surrogate endpoint must be validated at both individual-level and trial-level before it can be used to replace the clinical endpoint in a future clinical trial. Recently, meta-analytic methods for evaluating potential surrogates have become widely accepted in cancer clinical trials. In this review, after addressing multiple complications and general issues surrounding surrogate endpoints, we review various proposed and adopted meta-analytic methodologies pertaining to the application of these methods to oncology clinical trials with different tumor types. In oncology, several applications have successfully identified useful surrogates. For example, disease-free survival and progression-free survival have been validated through meta-analyses as acceptable surrogates for overall survival in adjuvant colon cancer and advanced colorectal cancer, respectively. We also discuss several limitations of surrogate endpoints, including the critical issues that the extrapolation of the validity of a surrogate is always context-dependent and that such extrapolation should be exercised with caution.

Key words

Evaluation of surrogate endpoint Meta-analysis Cancer clinical trial Progression-free survival Disease-free survival 

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References

  1. 1.
    Johnson JR, Temple R (1985) Food and Drug Administration requirements for approval of new anticancer drugs. Cancer Treat Rep 69:1155–1159PubMedGoogle Scholar
  2. 2.
    Fleming TR, DeMets DL (1996) Surrogate end points in clinical trials: are we being misled? Ann Intern Med 125:605–613PubMedGoogle Scholar
  3. 3.
    Schatzkin A (2000) Intermediate markers as surrogate endpoints in cancer research. Hematol Oncol Clin North Am 14:887–905PubMedCrossRefGoogle Scholar
  4. 4.
    Fleming TR (2005) Surrogate endpoints and FDA’s accelerated approval process. Health Aff (Millwood) 24:67–78CrossRefGoogle Scholar
  5. 5.
    Collette L, Burzykowski T, Schroder FH (2006) Prostate-specific antigen (PSA) alone is not an appropriate surrogate marker of long-term therapeutic benefit in prostate cancer trials. Eur J Cancer 42:1344–1350PubMedCrossRefGoogle Scholar
  6. 6.
    Ellenberg S, Hamilton JM (1989) Surrogate endpoints in clinical trials: cancer. Stat Med 8:405–413PubMedCrossRefGoogle Scholar
  7. 7.
    Herson J (1989) The use of surrogate endpoints in clinical trials (an introduction to a series of four papers). Stat Med 8:403–404CrossRefGoogle Scholar
  8. 8.
    Hillis A, Seigel D (1989) Surrogate endpoints in clinical trials: ophthalmologic disorders. Stat Med 8:427–430PubMedCrossRefGoogle Scholar
  9. 9.
    Prentice RL (1989) Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 8:431–440PubMedCrossRefGoogle Scholar
  10. 10.
    Wittes J, Lakatos E, Probstfield J (1989) Surrogate endpoints in clinical trials: cardiovascular diseases. Stat Med 8:415–425PubMedCrossRefGoogle Scholar
  11. 11.
    Boissel JP, Collet JP, Moleur P, et al (1992) Surrogate endpoints: a basis for a rational approach. Eur J Clin Pharmacol 43: 235–244PubMedCrossRefGoogle Scholar
  12. 12.
    Kosorok MR (1993) Using surrogate failure time data to increase cost effectiveness in clinical trials. Biometrika 80:823–833CrossRefGoogle Scholar
  13. 13.
    Fleming TR (1994) Surrogate markers in AIDS and cancer trials. Stat Med 13:1423–1435; discussion 1437–1440PubMedCrossRefGoogle Scholar
  14. 14.
    Temple RJ (1995) A regulatory authority’s opinion about surrogate endpoints. In: Nimmo WS, Tucker GT (eds) Clinical measurement in drug evaluation. John Wiley and Sons, New York, pp 1–22Google Scholar
  15. 15.
    De Gruttola V, Fleming T, Lin DY, et al. (1997) Perspective: validating surrogate markers-are we being naive? J Infect Dis 175:237–246PubMedGoogle Scholar
  16. 16.
    Lassere MN, Johnson KR, Boers M, et al. (2007) Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema. J Rheumatol 34:607–615PubMedGoogle Scholar
  17. 17.
    D’Agostino RB Jr (2000) Debate: the slippery slope of surrogate outcomes. Curr Control Trials Cardiovasc Med 1:76–78PubMedCrossRefGoogle Scholar
  18. 18.
    Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95CrossRefGoogle Scholar
  19. 19.
    Manns B, Owen WF Jr, Winkelmayer WC, et al. (2006) Surrogate markers in clinical studies: problems solved or created? Am J Kidney Dis 48:159–166PubMedCrossRefGoogle Scholar
  20. 20.
    Gluud C, Brok J, Gong Y, et al. (2007) Hepatology may have problems with putative surrogate outcome measures. J Hepatol 46:734–742PubMedCrossRefGoogle Scholar
  21. 21.
    US Department of Health and Human Services (2004) FDA: the nation’s premier consumer health protection agency. In: US Food and Drug Administration Washington, DCGoogle Scholar
  22. 22.
    US Department of Health and Human Services (2004) Guidance for industry: fast track drug development programs-designation, development, and application review. In: US Food and Drug Administration, Washington, DCGoogle Scholar
  23. 23.
    Katz R. (2004) Biomarkers and surrogate markers: an FDA perspective. NeuroRx®: J Am Soc Exp NeuroTher 1:189–195Google Scholar
  24. 24.
    Note for guidance on general considerations for clinical trials (CPMP/ICH/291/95). ICH Topic E 8: general considerations for clinical trials (2006)Google Scholar
  25. 25.
    Freud S (1910) The origin and development of psychoanalysis. Am J Psychol 21:181–218CrossRefGoogle Scholar
  26. 26.
    Wood PH (1983) Where are we now with radiographic assessment of rheumatoid arthritis? Br J Rheumatol 22:24–33PubMedGoogle Scholar
  27. 27.
    D’Agostino RB, Campbell MJ, Greenhouse JB (2006) Surrogate markers: back to the future. Stat Med 25:181–182PubMedCrossRefGoogle Scholar
  28. 28.
    Ray K, Sarkar PK (1999) Surrogate endpoints: do they really contribute in therapeutic decision making? J Assoc Physicians India 47:894–896PubMedGoogle Scholar
  29. 29.
    Johnston K (1999) What are surrogate outcome measures and why do they fail in clinical research? Neuroepidemiology 18: 167–173PubMedCrossRefGoogle Scholar
  30. 30.
    Psaty BM, Weiss NS, Furberg CD, et al. (1999) Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors for cardiovascular disease. JAMA 282:786–790PubMedCrossRefGoogle Scholar
  31. 31.
    Grimes DA, Schulz KF (2005) Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol 105: 1114–1118PubMedGoogle Scholar
  32. 32.
    Hemila H (2007) Small trials focusing on surrogate end points may be uninformative. Eur J Appl Physiol 99:707–708PubMedCrossRefGoogle Scholar
  33. 33.
    Hardman JG, Moppett IK, Mahajan RP (2008) Validity, credibility, and applicability: the rise and rise of the surrogate. Br J Anaesth 101:595–596PubMedCrossRefGoogle Scholar
  34. 34.
    De Gruttola VG, Clax P, DeMets DL, et al. (2001) Considerations in the evaluation of surrogate endpoints in clinical trials: summary of a National Institutes of Health Workshop. Control Clin Trials 22:485–502PubMedCrossRefGoogle Scholar
  35. 35.
    Baker SG, Kramer BS (2003) A perfect correlate does not a surrogate make. BMC Med Res Methodol 3:16PubMedCrossRefGoogle Scholar
  36. 36.
    Lipicky RJ, Packer M (1993) Role of surrogate end points in the evaluation of drugs for heart failure. J Am Coll Cardiol 22: 179A–184APubMedCrossRefGoogle Scholar
  37. 37.
    Altman DG (1994) The scandal of poor medical research. BMJ 308:283–284PubMedGoogle Scholar
  38. 38.
    Sobel BE, Furberg CD (1997) Surrogates, semantics, and sensible public policy. Circulation 95:1661–1663PubMedGoogle Scholar
  39. 39.
    Ridker PM, Torres J (2006) Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000–2005. JAMA 295:2270–2274PubMedCrossRefGoogle Scholar
  40. 40.
    Mansfield PR, Lexchin J, Wen LS, et al. (2006) Educating health professionals about drug and device promotion: advocates’ recommendations. PLoS Med 3:e451PubMedCrossRefGoogle Scholar
  41. 41.
    The Cardiac Arrhythmia Suppression Trial (CAST) Investigators (1989) Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 321:406–412Google Scholar
  42. 42.
    Weir CJ, Walley RJ (2006) Statistical evaluation of biomarkers as surrogate endpoints: a literature review. Stat Med 25:183–203PubMedCrossRefGoogle Scholar
  43. 43.
    Freedman LS, Graubard BI, Schatzkin A (1992) Statistical validation of intermediate endpoints for chronic diseases. Stat Med 11:167–178PubMedCrossRefGoogle Scholar
  44. 44.
    Lassere MN (2008) The Biomarker-Surrogacy Evaluation Schema: a review of the biomarker-surrogate literature and a proposal for a criterion-based, quantitative, multidimensional hierarchical levels of evidence schema for evaluating the status of biomarkers as surrogate endpoints. Stat Methods Med Res 17:303–340PubMedCrossRefGoogle Scholar
  45. 45.
    Burzykowski T, Molenberghs G, Buyse M (eds) (2005) The evaluation of surrogate endpoints (statistics for biology and health). Springer, Berlin Heidelberg New YorkGoogle Scholar
  46. 46.
    Lin DY, Fleming TR, De Gruttola V (1997) Estimating the proportion of treatment effect explained by a surrogate marker. Stat Med 16:1515–1527PubMedCrossRefGoogle Scholar
  47. 47.
    Buyse M, Molenberghs G (1998) Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics 54:1014–1029PubMedCrossRefGoogle Scholar
  48. 48.
    Molenberghs G, Buyse M, Geys H, et al. (2002) Statistical challenges in the evaluation of surrogate endpoints in randomized trials. Control Clin Trials 23:607–625PubMedCrossRefGoogle Scholar
  49. 49.
    Bycott PW, Taylor JM (1998) An evaluation of a measure of the proportion of the treatment effect explained by a surrogate marker. Control Clin Trials 19:555–568PubMedCrossRefGoogle Scholar
  50. 50.
    Flandre P, Saidi Y (1999) Estimating the proportion of treatment effect explained by a surrogate marker. Stat Med 18:107–109PubMedCrossRefGoogle Scholar
  51. 51.
    Buyse M, Molenberghs G, Burzykowski T, et al. (2000) Statistical validation of surrogate endpoints: problems and proposals. Drug Inf J 34:447–454Google Scholar
  52. 52.
    Molenberghs G, Burzykowski T, Alonso A, et al. (2004) A perspective on surrogate endpoints in controlled clinical trials. Stat Methods Med Res 13:177–206PubMedGoogle Scholar
  53. 53.
    Lassere M, Johnson K, Hughes M, et al. (2007) Simulation studies of surrogate endpoint validation using single trial and multitrial statistical approaches. J Rheumatol 34:616–619PubMedGoogle Scholar
  54. 54.
    Buyse M, Molenberghs G, Burzykowski T, et al. (2000) The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics 1:49–67PubMedCrossRefGoogle Scholar
  55. 55.
    Alonso A, Molenberghs G, Burzykowski T, et al. (2004) Prentice’s approach and the meta-analytic paradigm: a reflection on the role of statistics in the evaluation of surrogate endpoints. Biometrics 60:724–728PubMedCrossRefGoogle Scholar
  56. 56.
    Hughes MD (2002) Evaluating surrogate endpoints. Control Clin Trials 23:703–707PubMedCrossRefGoogle Scholar
  57. 57.
    Hughes MD, DeGruttola V, Welles SL (1995) Evaluating surrogate markers. J Acquir Immune Defic Syndr Hum Retrovirol 10(Suppl 2):S1–8PubMedGoogle Scholar
  58. 58.
    Daniels MJ, Hughes MD (1997) Meta-analysis for the evaluation of potential surrogate markers. Stat Med 16:1965–1982PubMedCrossRefGoogle Scholar
  59. 59.
    Gail MH, Pfeiffer R, Van Houwelingen HC, et al. (2000) On meta-analytic assessment of surrogate outcomes. Biostatistics 1:231–246PubMedCrossRefGoogle Scholar
  60. 60.
    van Houwelingen HC, Arends LR, Stijnen T (2002) Advanced methods in meta-analysis: multivariate approach and metaregression. Stat Med 21:589–624PubMedCrossRefGoogle Scholar
  61. 61.
    Alonso A, Molenberghs G (2007) Surrogate marker evaluation from an information theory perspective. Biometrics 63:180–186PubMedCrossRefGoogle Scholar
  62. 62.
    Tilahun A, Pryseley A, Alonso A, et al. (2008) Information theory-based surrogate marker evaluation from several randomized clinical trials with binary endpoints, using SAS. J Biopharm Stat 18:326–341PubMedCrossRefGoogle Scholar
  63. 63.
    Alonso A, Molenberghs G (2008) Evaluating time to cancer recurrence as a surrogate marker for survival from an information theory perspective. Stat Methods Med Res 17:497–504PubMedCrossRefGoogle Scholar
  64. 64.
    Pryseley A, Tilahun A, Alonso A, et al. (2007) Information-theory based surrogate marker evaluation from several randomized clinical trials with continuous true and binary surrogate endpoints. Clin Trials 4:587–597PubMedCrossRefGoogle Scholar
  65. 65.
    Sargent DJ, Wieand HS, Haller DG, et al. (2005) Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20 898 patients on 18 randomized trials. J Clin Oncol 23:8664–8670PubMedCrossRefGoogle Scholar
  66. 66.
    Sargent DJ, Patiyil S, Yothers G, et al. (2007) End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20 898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 25:4569–4574PubMedCrossRefGoogle Scholar
  67. 67.
    Baker SG (2006) A simple meta-analytic approach for using a binary surrogate endpoint to predict the effect of intervention on true endpoint. Biostatistics 7:58–70PubMedCrossRefGoogle Scholar
  68. 68.
    Baker SG (2008) Two simple approaches for validating a binary surrogate endpoint using data from multiple trials. Stat Methods Med Res 17:505–514PubMedCrossRefGoogle Scholar
  69. 69.
    Korn EL, Albert PS, McShane LM (2005) Assessing surrogates as trial endpoints using mixed models. Stat Med 24:163–182PubMedCrossRefGoogle Scholar
  70. 70.
    Abrahantes JC, Shkedy Z, Molenberghs G (2008) Alternative methods to evaluate trial level surrogacy. Clin Trials 5:194–208PubMedCrossRefGoogle Scholar
  71. 71.
    Burzykowski T, Buyse M (2006) Surrogate threshold effect: an alternative measure for meta-analytic surrogate endpoint validation. Pharm Stat 5:173–186PubMedCrossRefGoogle Scholar
  72. 72.
    Johnson JR, Williams G, Pazdur R (2003) End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 21:1404–1411PubMedCrossRefGoogle Scholar
  73. 73.
    Dagher R, Johnson J, Williams G, et al. (2004) Accelerated approval of oncology products: a decade of experience. J Natl Cancer Inst 96:1500–1509PubMedGoogle Scholar
  74. 74.
    Buyse M, Thirion P, Carlson RW, et al. (2000) Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Lancet 356:373–378PubMedCrossRefGoogle Scholar
  75. 75.
    Tang PA, Bentzen SM, Chen EX, et al. (2007) Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol 25:4562–4568PubMedCrossRefGoogle Scholar
  76. 76.
    Hackshaw A, Knight A, Barrett-Lee P, et al. (2005) Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer. Br J Cancer 93:1215–1221PubMedCrossRefGoogle Scholar
  77. 77.
    Burzykowski T, Buyse M, Piccart-Gebhart MJ, et al. (2008) Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol 26:1987–1992PubMedCrossRefGoogle Scholar
  78. 78.
    Burzykowski T, Buyse M, Yothers G, et al. (2008) Exploring and validating surrogate endpoints in colorectal cancer. Lifetime Data Anal 14:54–64PubMedCrossRefGoogle Scholar
  79. 79.
    Buyse M, Burzykowski T, Carroll K, et al. (2007) Progression-free survival is a surrogate for survival in advanced colorectal cancer. J Clin Oncol 25:5218–5224PubMedCrossRefGoogle Scholar
  80. 80.
    Miksad RA, Zietemann V, Gothe R, et al. (2008) Progression-free survival as a surrogate endpoint in advanced breast cancer. Int J Technol Assess Health Care 24:371–383PubMedCrossRefGoogle Scholar
  81. 81.
    Roessner M, De Wit R, Tannock IF (2005) Prostate-specific antigen (PSA) response as surrogate endpoint for overall survival (OS): analysis of the TAX 327 Study comparing docetaxel plus prednisone to mitoxantrone plus prednisone in advanced prostate cancer (abstract). J Clin Oncol 23:391sGoogle Scholar
  82. 82.
    Chakravarty A, Sridhara R (2008) Use of progression-free survival as a surrogate marker in oncology trials: some regulatory issues. Stat Methods Med Res 17:515–518PubMedCrossRefGoogle Scholar
  83. 83.
    Hughes MD (2008) Practical issues arising in an exploratory analysis evaluating progression-free survival as a surrogate endpoint for overall survival in advanced colorectal cancer. Stat Methods Med Res 17:487–495PubMedCrossRefGoogle Scholar
  84. 84.
    Powers JH (2005) Microbiologic surrogate end points in clinical trials of infectious diseases: example of acute otitis media trials. Pharmacotherapy 25:109S–123SPubMedCrossRefGoogle Scholar
  85. 85.
    Punt CJ, Buyse M, Kohne CH, et al. (2007) Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials. J Natl Cancer Inst 99:998–1003PubMedCrossRefGoogle Scholar
  86. 86.
    Stewart LA, Clarke MJ (1995) Practical methodology of meta-analyses (overviews) using updated individual patient data. Cochrane Working Group. Stat Med 14:2057–2079Google Scholar
  87. 87.
    Packer M, Carver JR, Rodeheffer RJ, et al. (1991) Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 325:1468–1475PubMedGoogle Scholar
  88. 88.
    Packers M, Rouleau J, Swedberg K, et al. (1993) Effect of Flosequinan on survival in chronic heart failure: Preliminary results of the PROFILE study (abstract). Circulation 88:I–301Google Scholar
  89. 89.
    Califf RM, Adams KF, McKenna WJ, et al. (1997) A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart J 134:44–54PubMedCrossRefGoogle Scholar
  90. 90.
    Hulley S, Grady D, Bush T, et al. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/ progestin Replacement Study (HERS) Research Group. JAMA 280:605–613PubMedCrossRefGoogle Scholar
  91. 91.
    Rossouw JE, Anderson GL, Prentice RL, et al. (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333PubMedCrossRefGoogle Scholar
  92. 92.
    The Writing Group for the PEPI Trial (1995) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 273:199–208CrossRefGoogle Scholar
  93. 93.
    Report of the Committee of Principal Investigators (1980) W.H.O. cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Lancet 2:379–385Google Scholar
  94. 94.
    Gordon DJ (1994) Cholesterol lowering and total mortality. In: Contemporary issues in cholesterol lowering: clinical and population aspects. Marcel Dekker, New YorkGoogle Scholar
  95. 95.
    Riggs BL, Hodgson SF, O’Fallon WM, et al. (1990) Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 322:802–8029PubMedGoogle Scholar
  96. 96.
    Aboulker JP, Swart AM, Committee CC (1993) Preliminary analysis of the Concorde trial. Lancet 341:889–890PubMedCrossRefGoogle Scholar
  97. 97.
    Baker SG, Izmirlian G, Kipnis V (2005) Resolving paradoxes involving surrogate end points. J R Stat Soc Ser A Stat Soc 168:753–762CrossRefGoogle Scholar
  98. 98.
    Renard D, Geys H, Molenberghs G, et al. (2002) Validation of surrogate endpoints in multiple randomized clinical trials with discrete outcomes. Biom J 44:921–935CrossRefGoogle Scholar
  99. 99.
    Molenberghs G, Geys H, Buyse M (2001) Evaluation of surrogate endpoints in randomized experiments with mixed discrete and continuous outcomes. Stat Med 20:3023–3038PubMedCrossRefGoogle Scholar
  100. 100.
    Burzykowski T, Molenberghs G, Buyse M (2004) The validation of surrogate end points by using data from randomized clinical trials: a case-study in advanced colorectal cancer. J R Stat Soc Ser A Stat Soc 167:103–124CrossRefGoogle Scholar
  101. 101.
    Burzykowski T, Molenberghs G, Buyse M, et al. (2001) Validation of surrogate end points in multiple randomized clinical trials with failure time end points. J Appl Stat 50:405–422Google Scholar
  102. 102.
    Renard D, Geys H, Molenberghs G, et al. (2002) Validation of longitudinally measured surrogate marker for a time-to-event endpoint. J Appl Stat 30:235–247Google Scholar
  103. 103.
    Buyse M, Vangeneugden T, Bijnens L, et al. (2003) Validation of biomarkers as surrogates for clinical endpoints. Marcel Dekker, New YorkGoogle Scholar
  104. 104.
    Newling D, Carroll K, Morris T (2004) Is prostate-specific antigen progression a surrogate for objective clinical progression in early prostate cancer? (abstract) J Clin Oncol 22:4652CrossRefGoogle Scholar
  105. 105.
    Collette L, Burzykowski T, Carroll KJ, et al. (2005) Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals. J Clin Oncol 23:6139–6148PubMedCrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2009

Authors and Affiliations

  1. 1.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA

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