1. Adam Seegmiller, MD, PhD Assistant Professor of Pathology, Microbiology, and Immunology Executive Medical Director of Clinical Pathology Director, Divisions of Hematopathology and Laboratory Medicine Vanderbilt University School of Medicine Nashville, TN The Hematopathology Diagnostic Management Team (DMT) The Right Test for the Right Patient at the Right Time

2. The Diagnostic Management Team Right Test, Right Patient, Right time  Diagnostic Challenges in Personalized Medicine  DMT Definition, Design, and Implementation  Impact and Outcomes  Future Applicability

3. Personalized (Precision) Medicine “Personalized medicine is the combination of established clinical parameters with emerging molecular information to generate preventative, diagnostic and therapeutic solutions that are tailored to each patient’s needs. Personalized approaches facilitate more precise healthcare delivery and have the potential to improve outcomes while reducing waste of resources and delivering significant other benefits.” www.weforum.org/reports/preparing-precision-medicine

4. The Traditional Model of Pathology: Clinician Lab(s) Clinician Clinician orders individual tests Lab(s) perform ordered tests and return simple results Clinician collates and interprets results alone

5. Diagnosis Prognosis Monitoring FISH (many) Immunohistochemistry Flow Cytometry Karyotype Morphology Molecular Tests (many) Complexity of Diagnostic Testing in Hematopathology

6. Patient presents with pancytopenia and circulating blasts → suspect AML BiopsyAspirate Cytogenetics Molecular Pathology Clinician orders bone marrow biopsy with: Flow cytometry Karyotype FISH (MDS and AML Panels) Molecular tests (FLT3, NPM1, c-Kit, CEBPA) Bone Marrow Biopsy FISH x4Karyotype Hematopathology Immunopathology Morphologic exam Flow Cytometry NPM1FLT3 AMLNormalNegative x8PositiveNegative Clinician receives and interprets reports Induction Chemotherapy Initiated Outside Laboratory CEBPAc-Kit Negative Large Test Menu Few Guidelines Multiple Laboratories Multiple Asynchronous Reports Complex Interpretation Not simple positive or negative Context-dependent Interaction between tests Multiple Iterations

7. The Traditional Model of Pathology: Limitations for Personalized Medicine Clinician Lab(s) Clinician ChallengesConsequences Large, complex test menus Few guidelines for test selection Unnecessary tests = increased costs Missed tests = insufficient information Multiple laboratories Multiple asynchronous reports Inefficient work-flow = wasted time Complex diagnostic outcomes. Difficult to correlate and interpret results Clinician orders individual tests Lab(s) perform ordered tests and return simple results Clinician collates and interprets results alone

8. The Diagnostic Management Team Right Test, Right Patient, Right time  Diagnostic Challenges in Personalized Medicine  DMT Definition, Design, and Implementation  Impact and Outcomes  Future Applicability

9. Collaborative effort between pathologists, hematologists, and bioinformaticians… 1.To develop the right pattern of diagnostic testing for the right patient—the most cost effective personalized medicine. 2.To design informatics tools to enhance communication between clinicians and pathologists. 3.To create a single, evidence-based, summative report of all integrative diagnostic data to guide therapy and disease monitoring. Diagnostic Management Team (DMT)

10. LabClinicianDMT Clinician Unnecessary tests deleted Essential tests added Standard Ordering Protocols (SOPs) Comprehensive Reports

11. Standard Ordering Protocols (SOPs) Designed by teams: – Hematologists and pathologists. – Refined and agreed-upon by all providers. Specific to type of disease and stage of therapy Evidence based: – Published literature and clinical guidelines. – Agreed-upon best clinical practices. Principles: – Tests should be ordered at diagnosis if useful for diagnosis, prognosis, monitoring, or therapy. – Tests should be ordered at follow-up if: (1) they were positive at diagnosis, (2) they are sensitive for residual disease detection, and (3) they represent the most sensitive testing modality.

12. Patient presents with pancytopenia and circulating blasts → suspect AML Clinician orders bone marrow biopsy with Bone marrow testing panel (DMT)** Bone Marrow Biopsy Hematopathology Immunopathology Morphologic exam Flow Cytometry Pathologist: 1.Reviews order form and patient history 2.Evaluates morphology and flow cytometry 3.Orders ancillary tests based on SOPs 4.Issues preliminary report AML Cytogenetics Molecular Pathology FISH x8KaryotypeNPM1FLT3 NormalNegative x8PositiveNegative Outside Laboratory CEBPAc-Kit Negative **Clinicians are allowed to opt out and order tests a la carte.

13. Communication Challenges Pathologist What is the patient’s history? – Does the patient have a diagnosis? What is it? – Is this a new sample? A follow-up after therapy or transplant? Has the patient had prior testing? What were the results? Clinician What tests were ordered for this patient? What is the status of the tests? What are the results? What do they mean?

14. Electronic Testing Form gives clinical context

15. Flowsheet helps with clinical and testing history

16. Dashboard communicates testing status Status indicators: v = pending green = all tests in category resulted yellow = some resulted, some pending Dashboard also provides secure messaging

17. Patient presents with pancytopenia and circulating blasts → suspect AML Clinician orders bone marrow biopsy with Bone marrow testing panel (DMT)** Bone Marrow Biopsy Hematopathology Immunopathology Morphologic exam Flow Cytometry Pathologist: 1.Reviews order form and patient history 2.Evaluates morphology and flow cytometry 3.Orders ancillary tests based on SOPs 4.Issues preliminary report AML Cytogenetics Molecular Pathology FISH x8KaryotypeNPM1FLT3 NormalNegative x8PositiveNegative Outside Laboratory CEBPAc-Kit Negative **Clinicians are allowed to opt out and order tests a la carte. Pathologist generates comprehensive report that includes: 1.Summary of all test results. 2.Comprehensive diagnosis.

18. Comprehensive Hematopathology Reports Comprehensive diagnosis accounting for all test results Personalized diagnostic, prognostic, and therapeutic information Report fields are automatically populated by data from individual reports

19. Communication Challenges Pathologist What is the patient’s history? Testing form – Does the patient have a diagnosis? What is it? – Is this a new sample? A follow-up after therapy or transplant? Has the patient had prior testing? What were the results? Patient flowsheet Clinician What tests were ordered for this patient? What is the status of the tests? Testing Dashboard What are the results? What do they mean? Comprehensive Report

20. The Diagnostic Management Team Right Test, Right Patient, Right time  Diagnostic Challenges in Personalized Medicine  DMT Definition, Design, and Implementation  Impact and Outcomes  Future Applicability

21. What would a successful DMT look like? Clinicians would express confidence in the system. – This confidence would be reflected in their voluntary utilization of the DMT. Confident Efficient Effective Evolving The system would be more efficient. – Diagnostic latency would be decreased, leading to more timely therapy. Testing guidelines would evolve as evidence for best practices accumulates. Improved test utilization and performance – Fewer unnecessary tests, fewer omitted tests, more positive tests.

22. Confident: DMT was accepted by users Survey of 34 clinicians (22 responses) who ordered the hematopathology DMT at Vanderbilt.

23. Confident: DMT was accepted by users Bone Marrow Testing Panel Clinician “a la carte” Fractional weekly utilization of the bone marrow testing panel vs. a la carte ordering after DMT implementation.

24. Efficient: DMT saves clinicians time 23 Survey of 34 clinicians (22 responses) who ordered the hematopathology DMT at Vanderbilt. Median savings = 5 min/patient

25. Effective: Utilization Before DMT Total Tests / Marrow 3.7 Discordant 1.3 Concordant 2.4 Omitted 0.4 Ideal 2.8 Excess Tests (1.0, 26%) Conclusions: Prior to DMT we performed 26% more tests than are necessary. A significant number of marrows were missing essential tests.

26. Effective: DMT Reduces Unnecessary Tests Pre-DMTPost-DMT *** * ↓ 69%

27. Effective: DMT Reduces Omitted Tests Pre-DMTPost-DMT ** *** ** ↓ 88% **

28. Fewer Tests with No Loss of Data Is there a negative clinical impact to reduced testing? Are we losing important information by eliminating tests? TestsTotalPositive Total6,5621,300 (20%) Concordant4,5881,221 (27%) Discordant1,97479 (4%) Combined prospective / retrospective analysis Discordant Positives 43 (2.2%) Redundant 13 (0.6%) Low-level, unique 13 (0.6%) MDS karyotype 10 (0.5%) MRD

29. Effective: DMT Increases Positive Test Rate Pre-DMTPost-DMT ↑ 75% ** After DMT implementation, tests are more likely to be meaningful, there is increased positive predictive value, and less likelihood of false positives.

30. DMT Decreases Costs Over the 1 st year of implementation, total tests decreased 15%. The average cost of testing to payers (insurers/Medicare) decreased by $442 per marrow (95% CI = $290-$594). The total annual savings was approximately $500,000 - $1,000,000 on an annual volume of 1800 bone marrows. Potential annual savings are ~$191 - $392 million at the national level on an estimated 666,000 bone marrows.

31. Evolving: DMT as a Rapid Learning System Initial SOP Results and Utilization Data Analysis Revised SOPs Abernathy et al., J Clin Oncol, 2010;28:4268

32. Evolving: The DMT “Learns” Example: Bone Marrow Failure Initial SOP (#1) Karyotype MDS FISH Panel: 5q, 7q, +8, 20q Total Tests Positive Tests Before2645 (2%) After SOP#1 44113 (3%) After SOP#2 1504 (3%) Data Analysis FISH and karyotype are redundant. Revised SOP (#2) Karyotype

33. Evolving: The DMT “Learns”

34. Summary: Benefits of the DMT Increased efficiency of care for both clinicians and pathologists Standardized test ordering procedures Decreased unnecessary tests, decreasing cost Decreased omission of necessary tests Created a rapid learning system for continuous refinement and improvement of guidelines that can accommodate changing test menus Accepted by clinical partners and enhanced clinical communication and cooperation Transformed the clinical environment and its operations

35. The Diagnostic Management Team Right Test, Right Patient, Right time  Diagnostic Challenges in Personalized Medicine  DMT Definition, Design, and Implementation  Impact and Outcomes  Future Applicability

36. Expansion of DMT to Other Services Coagulation: DMT successfully functioning at Vanderbilt since 2010 Hemepath: DMT pilot successfully running regionally since 2011 Microbiology: “DMT lite” leverages similar concept for efficiencies, running since 2011 Blood Bank: “DMT lite” leverages similar concept for efficiencies, running since 2011 Breast Cancer: Currently in design phase Ultimately applicable to all diseases requiring complex diagnostics

37. Acknowledgements Pathology Mary Zutter, MD Samuel Santoro, MD, PhD Michael Laposata, MD, PhD Annette Kim, MD, PhD Megan Kressin, MD Claudio Mosse, MD, PhD Mary Ann Thompson-Arildson, MD, PhD David Head, MD Shaoying Li, MD Aaron Shaver, MD, PhD Bruce Greig, MT(ASCP) Holly Pinder, MT(ASCP) Fellows and Residents Adult Hematology Madan Jagasia, MBBS Nishitha Reddy, MD Stephen Strickland, MD, MSCI David Morgan, MD Sanjay Mohan, MD Michael Savona, MD Pediatric Hematology Debra Friedman, MD Haydar Frangoul, MD Scott Borinstein, MD, PhD Administration William Stead, MD Kristy Sinkfield, MEd Herschel Pollard, MS Lauren McConville Ed Marx, MBA Mengfei Huang, MSc Informatics Mia Levy, MD, PhD Ed Shultz, MD, MS Shannon Rich Perry Adams Kevin Cole Matthew Montgomery Jameson Porter Naqi Khan, MD Dario Giuse, Dr.Ing. Jonathan Grande Biostatistics William Dupont Dale Plummer