Simple. Scientifically Informed Medical Practice and Learning Suzana Alves da Silva, MD, MSc, PhD, FNYAM 2014 TEACH Workshop THE SECTION ON Evidence Based Health Care OF THE NEW YORK ACADEMY OF MEDICINE

Therapy Diagnosis Prognosis Harm What we know? What is the magnitude of benefit offered or harm caused by the intervention? What is the effect of an specific condition on patients response to the intervention or exposure? What is the effect of the prognostic factor on the risk? What is the accuracy of the test to predict the disease? What is the actual risk if submitted to the intervention or exposure? What is the actual risk if the condition is present? What is the most frequent cause for this symptoms? PICO 2 Clinical Problems Chatterji, M; Graham, M; Wyer, P. Mapping Cognitive Overlaps Between Practice-Based Learning and Improvement and Evidence-Based Medicine: An Operational Definition for Assessing Resident Physician Competence. 2009

LikelihoodPerformanceUtility What is the magnitude of benefit offered or harm caused by the intervention? What is the effect of an specific condition on patients response to the intervention or exposure? What is the effect of the prognostic factor on the risk? What is the accuracy of the test to predict the disease? What is the actual risk if submitted to the intervention or exposure? What is the actual risk if the condition is present? What is the most frequent cause for this symptoms? What is new? 3 Impact on outcome Prediction of outcome Frequency of outcome Therapy Diagnosis Prognosis Harm Silva, S and Wyer P. The Roadmap: a blueprint for evidence literacy within a Scientifically Informed Medical Practice and Learning Model. 2012

Why this is so important? 4

Likelihood issue on therapy An elderly man is brought to the emergency room from a nursing home. He is febrile, hypotensive, anuric, minimally responsive. Medical and nursing staffs are preparing to implement an advanced protocol for sepsis care when the patient’s daughter arrives. The daughter wants to know “So, if you give him the most intense treatment, how likely is it that he will survive? It doesn’t make sense if he is likely to die anyway!” 5 This scenario converges on an issue of the absolute probability of survival given maximal, evidence-based, interventions.

Utility issue on prognosis A 40 year old woman is seeing her primary care physician. Her mother has recently been diagnosed with Alzheimer’s disease. She is concerned about the possibility that it could happen to her. The physician advises that there is a genetic test that could eliminate that likelihood. However, the woman expresses ambivalence, saying, “I am not sure I want to know.” 6 This scenario involves a trade-off between risks versus benefits of sharing the results of a prognostic information.

Performance issue on therapy A medical director of a health care organization is considering inclusion of BRCA1 within a panel of molecular biomarkers for optimization of individualized care of women with diagnosed breast cancer with respect to hormonal therapy, immune-therapy or chemo-therapy. His first question is what is the accuracy of BRCA1 mutation to predict that a women with cancer will in fact respond to a specific therapeutic regimen. 7 This scenario involves predicting the likelihood of benefit from a treatment if the predictor is present. It calls for information regarding the predictive performance of criteria such as a biomarker in modifying the probability of benefit from a therapeutic option.

Levels of efficacy of Dx imaging tests 1. Proof of concept—Do novel marker levels differ between subjects with and without outcome? 2. Prospective validation—Does the novel marker predict development of future outcomes? 4. Clinical utility—Does the novel risk marker change predicted risk sufficiently to change recommended therapy and to improve clinical outcomes? 6. Cost-effectiveness—Does use of the marker justify additional costs of testing and treatment? Phases of novel cardiac markers diagnostic accuracy, sensitivity, and specificity associated with interpretation of the test. whether the information produces change in the referring physician’s diagnostic thinking. effect of the information on the patient management plan and on patient outcomes. societal costs and benefits of a diagnostic imaging technology. 8 Hlatky. AHA 2009Fryback and Thornbury Likeli hood Perfor mance Utility Likeli hood Perfor mance Utility Perfor mance Utility Perfor mance Utility

9 = Randomized Trials

10

11 “My doctors estimated that I had an 87 percent risk of breast cancer and a 50 percent risk of ovarian cancer… Once I knew that this was my reality, I decided to be proactive and to minimize the risk as much as I could.”

Scenario 12 Chief Medical Executive Physician Healthy Patient HMOs being pressured for the inclusion of BRCA mutation testing for screening of women with high risk of breast cancer. Many primary care physicians are ordering BRCA mutation testing to their patients or referring them for genetic counseling without knowing exactly what to do with it. Many patients with family history of cancer want to be tested for BRCA mutation. Many wonder about preventive surgery or chemotherapy on top of surveillance.

BRCA1 for screening 13 ExecutivePhysicianPatient How the organization will support that Costs? Medical staffs? Reliability Costs, who pays? Screening criteria Prevalence Performance Descendings? Screening versus surgery? Mortality morbidity QOL

BRCA1 for screening 14 ExecutivePhysicianPatient L How many women with high risk of breast cancer? How likely is the development of breast cancer if BRCA1(+) and (-)? How many litigations? What is the uncertainty of the information on the risk of breast cancer? Does it apply to this patient? What is my risk of breast cancer? P How accurate is BRCA1 mutation to predict breast cancer in such groups of women? For how many times the presence of BRCA1 increases my risk of breast cancer? U If we tested them all for BRCA1 mutation, would it decrease costs? Preventive mastectomy would decrease the risk? If so, for how much? Should I do preventive mastectomy to minimize my risk?

15 Source: 1. Senkus. European Society of Medical Oncology Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: U.S. Preventive Services Task Force Recommendation Berliner. National Society of Genetic Counselors 2013 Breast Cancer || Ovarian Cancer Women in general Preventive surgery will drop the risk of cancer by ~ 90% Little info about the effect of chemoprevention or close surveillance Little info about impact on death

Why this is so important? Recognition of questions of importance to patients, managers and policy makers in a fashion that facilitates the use of clinical research to inform the corresponding decisions. Provide guidance regarding how to explore and interpret patient and stakeholder expressions of the concerns that will maximally inform decisions. Categorization of clinical research designs in relationship to different types of clinical questions in a way that embraces the full spectrum of clinically relevant research. 16

Why this is so important? 17

Thank you! 18

Therapy Utility In high risk patients, BRCA1+, for how much preventive surgery compared to surveillance decreases patient important outcomes? Therapy Frequency In BRCA1+ patients who are submitted to preventive surgery what is the expected likelihood of cancer and death? 19

Prognosis Utility In high risk patients, does BRCA mutation testing compared to usual care decrease patient important outcomes? Prognosis Frequency In high risk patients, who are BRCA1+ carriers what is the expected likelihood of cancer and death? 20