Jesse Burk-Rafel

Population Screening for Variant Creutzfeldt-Jakob Disease Using a Novel Blood Test: Diagnostic Accuracy and Feasibility Study

IMPORTANCE Our study indicates a prototype blood-based variant Creutzfeldt-Jakob disease (vCJD) assay has sufficient sensitivity and specificity to justify a large study comparing vCJD prevalence in the United Kingdom with a bovine spongiform encephalopathy-unexposed population. In a clinical diagnostic capacity, the assays likelihood ratios dramatically change an individuals pretest disease odds to posttest probabilities and can confirm vCJD infection. OBJECTIVES To determine the diagnostic accuracy of a prototype blood test for vCJD and hence its suitability for clinical use and for screening prion-exposed populations. DESIGN, SETTING, AND PARTICIPANTS Retrospective, cross-sectional diagnostic study of blood samples from national blood collection and prion disease centers in the United States and United Kingdom. Anonymized samples were representative of the US blood donor population (n = 5000), healthy UK donors (n = 200), patients with nonprion neurodegenerative diseases (n = 352), patients in whom a prion disease diagnosis was likely (n = 105), and patients with confirmed vCJD (n = 10). MAIN OUTCOME AND MEASURE Presence of vCJD infection determined by a prototype test (now in clinical diagnostic use) that captures, enriches, and detects disease-associated prion protein from whole blood using stainless steel powder. RESULTS The assays specificity among the presumed negative American donor samples was 100% (95% CI, 99.93%-100%) and was confirmed in a healthy UK cohort (100% specificity; 95% CI, 98.2%-100%). Of potentially cross-reactive blood samples from patients with nonprion neurodegenerative diseases, no samples tested positive (100% specificity; 95% CI, 98.9%-100%). Among National Prion Clinic referrals in whom a prion disease diagnosis was likely, 2 patients with sporadic CJD tested positive (98.1% specificity; 95% CI, 93.3%-99.8%). Finally, we reconfirmed but could not refine our previous sensitivity estimate in a small blind panel of samples from unaffected individuals and patients with vCJD (70% sensitivity; 95% CI, 34.8%-93.3%). CONCLUSIONS AND RELEVANCE In conjunction with the assays established high sensitivity (71.4%; 95% CI, 47.8%-88.7%), the extremely high specificity supports using the assay to screen for vCJD infection in prion-exposed populations. Additionally, the lack of cross-reactivity and false positives in a range of nonprion neurodegenerative diseases supports the use of the assay in patient diagnosis.

A highly specific blood test for vCJD.

To the editor: Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disease originating from exposure to bovine spongiform encephalopathy (BSE). Despite low clinical incidence, the risk of secondary vCJD infection via blood transfusions from subclinical carriers persists. A recent

Engaging Learners to Advance Medical Education.

Learners are a pillar of academic medicine, yet their voice is seldom heard in national and international scholarly conversations on medical education. However, learners are eager to contribute: in response to a recent open call from Academic Medicine, medical students and residents representing 98 institutions across 11 countries submitted 224 Letters to the Editor on wide-ranging topics. In this Invited Commentary, the authors-three medical students serving in national leadership roles-contextualize several themes discussed in these learner-authored letters.The authors first explore the unique voice learners contribute to educational innovation, highlighting the value learners add to curricular and systemic educational reform efforts. They then turn to the broader implications of the many submitted letters addressing the culture and humanism of medicine, proposing that learners can be powerful catalysts and partners in cultural change. Despite these benefits, the authors note that learners are largely untapped change agents who are particularly underrepresented in medical education scholarship, finding that students were just 2.8% (39/1,396) of authors and 3.5% (12/340) of first authors among all print publications in Academic Medicine in 2016. The authors conclude by offering tangible steps for the academic medical community to engage learners in leadership, advocacy, and scholarship.

Scholarly concentration program development: A generalizable, data-driven approach

Purpose Scholarly concentration programs—also known as scholarly projects, pathways, tracks, or pursuits—are increasingly common in U.S. medical schools. However, systematic, data-driven program development methods have not been described. Method The authors examined scholarly concentration programs at U.S. medical schools that U.S. News & World Report ranked as top 25 for research or primary care (n = 43 institutions), coding concentrations and mission statements. Subsequently, the authors conducted a targeted needs assessment via a student-led, institution-wide survey, eliciting learners’ preferences for 10 “Pathways” (i.e., concentrations) and 30 “Topics” (i.e., potential content) augmenting core curricula at their institution. Exploratory factor analysis (EFA) and a capacity optimization algorithm characterized best institutional options for learner-focused Pathway development. Results The authors identified scholarly concentration programs at 32 of 43 medical schools (74%), comprising 199 distinct concentrations (mean concentrations per program: 6.2, mode: 5, range: 1–16). Thematic analysis identified 10 content domains; most common were “Global/Public Health” (30 institutions; 94%) and “Clinical/Translational Research” (26 institutions; 81%). The institutional needs assessment (n = 468 medical students; response rate 60% overall, 97% among first-year students) demonstrated myriad student preferences for Pathways and Topics. EFA of Topic preferences identified eight factors, systematically related to Pathway preferences, informing content development. Capacity modeling indicated that offering six Pathways could guarantee 95% of first-year students (162/171) their first- or second-choice Pathway. Conclusions This study demonstrates a generalizable, data-driven approach to scholarly concentration program development that reflects student preferences and institutional strengths, while optimizing program diversity within capacity constraints.

New Medical Student Performance Evaluation Standards: Laudable but Inadequate

1 National Resident Matching Program. Charting outcomes in the Match, 2016. http://www.nrmp.org/match-data/mainresidency-match-data/. Accessed February 27, 2017. 2 National Resident Matching Program. NRMP historical reports: Results and data: Main Residency Match. http://www.nrmp. org/match-data/nrmp-historical-reports/. Accessed February 27, 2017. 3 National Resident Matching Program. Results of the 2016 NRMP Program Director Survey. http://www.nrmp.org/wp-content/ uploads/2016/09/NRMP-2016-ProgramDirector-Survey.pdf. Published June 2016. Accessed February 21, 2017. 4 Otero HJ, Erturk SM, Ondategui-Parra S, Ros PR. Key criteria for selection of radiology residents: Results of a national survey. Acad Radiol. 2006;13:1155–1164. category containing 3% to 39% of students at different institutions. Lower grade and ranking categories display even greater between-institution variability. Even with improved transparency, how can residency program directors appropriately compare students from different institutions whose grades and ranks represent drastically different performance percentiles? Most concerning, if no statistically valid way to compare such measures exists, what heuristics are programs using? In our interactions with students across diverse institutions, many have voiced these or similar concerns. Students from institutions with stringent grading distributions are especially vocal in their concern for inequity. Thus, while the MSPE recommendations may better expose underlying between-school variability, they ultimately fail to address the fundamental challenge: nonstandardization in grading and ranking.

Blood test for variant Creutzfeldt-Jakob disease--reply.

Blood Test for Variant Creutzfeldt-Jakob Disease To the Editor Jackson et al1 reported significant advances in the detection of abnormal prion protein in blood. These could prove helpful in developing strategies to mitigate the risk for variant Creutzfeldt-Jakob disease (vCJD) being transmitted via blood transfusion, as happened in the United Kingdom in 3 known instances in or before 1999. However, care is needed in interpreting test performance, even assuming that a truepositive result necessarily indicates vCJD infection (differing views on which are reflected in the Food and Drug Administration assessment of vCJD risk to US blood recipients2). The results reported by Jackson et al1 suggest a test sensitivity of about 70% and a possible specificity of 99.97% (a falsepositive rate of about 1 in 3000) once the test is repeated. The latter is a theoretical figure derived from finding no repeat reactives in a relatively small control study. The article then turns to the key question of positive predictive value (PPV), considering what a repeat reactive result would mean if true prevalence of vCJD were 1 in 2000, as suggested by a recent survey of UK appendix samples.3 It refers to a PPV of about 78% (where 78% of positive results would be true) and an unwary reader could understand this to refer to a test with the performance figures just given. However, this is not the case. To illustrate, consider a population with a true prevalence of 1 in 2000—for convenience, say 10 infected and 20 000 not. When tested, the former would be expected to yield 7 truepositive results, while the latter would give 6 false-positive results. With almost as many false-positive results as true, the resulting PPV would be 54%. As more careful reading of the article clarifies, the 78% PPV refers to a theoretical scenario with test sensitivity of 100%. (By coincidence, a similar PPV would be achieved with specificity of 99.7% and 100% sensitivity.) How important this is depends greatly on how the test may be used. For an unlinked, anonymized prevalence study analogous to tissue surveys already undertaken, the incidence of false-positive results is less critical. By contrast, it is a key consideration when contemplating the introduction of a screening test for blood donations, when positive results lead to loss of donations and a duty to inform donors of the news is liable to cause considerable distress but with unknown implications for their future health.4