Changes in Circulating Tumor DNA Reflect Clinical Benefit Across Multiple Studies of Patients With Non-Small-Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

PURPOSE: As immune checkpoint inhibitors (ICI) become increasingly used in frontline settings, identifying early indicators of response is needed. Recent studies suggest a role for circulating tumor DNA (ctDNA) in monitoring response to ICI, but uncertainty exists in the generalizability of these studies. Here, the role of ctDNA for monitoring response to ICI is assessed through a standardized approach by assessing clinical trial data from five independent studies. PATIENTS AND METHODS: Patient-level clinical and ctDNA data were pooled and harmonized from 200 patients across five independent clinical trials investigating the treatment of patients with non-small-cell lung cancer with programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1)-directed monotherapy or in combination with chemotherapy. CtDNA levels were measured using different ctDNA assays across the studies. Maximum variant allele frequencies were calculated using all somatic tumor-derived variants in each unique patient sample to correlate ctDNA changes with overall survival (OS) and progression-free survival (PFS). RESULTS: We observed strong associations between reductions in ctDNA levels from on-treatment liquid biopsies with improved OS (OS; hazard ratio, 2.28; 95% CI, 1.62 to 3.20; P < .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36; P < .001). Changes in the maximum variant allele frequencies ctDNA values showed strong association across different outcomes. CONCLUSION: In this pooled analysis of five independent clinical trials, consistent and robust associations between reductions in ctDNA and outcomes were found across multiple end points assessed in patients with non-small-cell lung cancer treated with an ICI. Additional tumor types, stages, and drug classes should be included in future analyses to further validate this. CtDNA may serve as an important tool in clinical development and an early indicator of treatment benefit.

Quantitative PCR-Based Method to Assess Cell-Free DNA Quality, Adjust Input Mass, and Improve Next-Generation Sequencing Assay Performance.

Cell-free (cf)DNA-based testing has undergone increasingly wide adoption, including assays for the detection of circulating tumor DNA. Due to nucleosome protection, cfDNA has a distinctive fragment size of 160 to 180 bp. However, cfDNA can be contaminated with high molecular weight genomic DNA from blood cells released in plasma during sample collection. Such contamination can lead to decreased sensitivity or inconsistent results in cfDNA next-generation sequencing assays. This article describes a technical advancement in which a quantitative PCR method is used for high molecular weight contamination assessment and input mass adjustment, and has been demonstrated to improve consistency of performance in a circulating tumor DNA next-generation sequencing workflow.

Biological and technical factors in the assessment of blood-based tumor mutational burden (bTMB) in patients with NSCLC.

BACKGROUND: Patients treated with immunotherapy are at risk of considerable adverse events, and the ongoing struggle is to accurately identify the subset of patients who will benefit. Tumor mutational burden (TMB) has emerged as a promising predictive biomarker but requires tumor tissue which is not always available. Blood-based TMB (bTMB) may provide a minimally invasive assessment of mutational load. However, because of the required sequencing depth, bTMB analysis is costly and prone to false negative results. This study attempted to design a minimally sized bTMB panel, examined a counting-based method for bTMB in patients with stage I to IV non-small cell lung cancer (NSCLC) and evaluated both technical factors such as bTMB and tissue-based TMB (tTMB) cut-off, as well as sample-related factors such as cell-free DNA input mass which influence the correlation between bTMB and tTMB. METHODS: Tissue, plasma, and whole blood samples collected as part of the LEMA trial (NCT02894853) were used in this study. Samples of 185 treatment naïve patients with stage I to IV NSCLC were sequenced at the Roche Sequencing Solutions with a custom panel designed for TMB, using reagents and workflows derived from the AVENIO Tumor Tissue and circulating tumor DNA Analysis Kits. RESULTS: A TMB panel of 1.1 Mb demonstrated highly accurate TMB high calls with a positive predictive value of 95% when using a tTMB cut-off of 16 mut/Mb, corresponding with 42 mut/Mb for bTMB. The positive per cent agreement (PPA) of bTMB was relatively low at 32%. In stage IV samples with at least 20 ng of cfDNA input, PPA of bTMB improved to 63% and minimizing the panel to a subset of 577 kb was possible while maintaining 63% PPA. CONCLUSION: Plasma samples with high bTMB values are highly correspondent with tTMB, whereas bTMB low results may also be the result of low tumor burden at earlier stages of disease as well as poorly shedding tumors. For advanced stages of disease, PPA (sensitivity) of bTMB is satisfactory in comparison to tTMB, even when using a panel of less than 600 kb, warranting consideration of bTMB as a predictive biomarker for patients with NSCLC eligible for immunotherapy in the future.

ALK Mutation Status Before and After Alectinib Treatment in Locally Advanced or Metastatic ALK-Positive NSCLC: Pooled Analysis of Two Prospective Trials.

INTRODUCTION: The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies. METHODS: Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA from 187 patients post-crizotinib/pre-alectinib, and from 49 of these patients who subsequently progressed on alectinib. RESULTS: Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48 of 187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI]: 8.1-14.3) versus 5.6 months (95% CI: 4.5-10.9), respectively. Sixteen of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to alectinib (all partial responses); most of these ALK mutations were known to be sensitive to alectinib. Analysis of plasma samples obtained post-progression on alectinib revealed that 26 of 49 (53%) samples harbored 16 distinct ALK mutations, with known alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15 of 49 (31%) tumors. CONCLUSIONS: Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy.

Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA.

Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

Integrated digital error suppression for improved detection of circulating tumor DNA.

High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

Identification and genetic manipulation of human and mouse oesophageal stem cells.

OBJECTIVE: Human oesophageal stem cell research is hampered by the lack of an optimal assay system to study self-renewal and differentiation. We aimed to identify and characterise human and mouse oesophageal stem/progenitor cells by establishing 3-dimensional organotypic sphere culture systems for both species. DESIGN: Primary oesophageal epithelial cells were freshly isolated and fluorescence-activated cell sorting (FACS)-sorted from human and mouse oesophagus and 3-dimensional organotypic sphere culture systems were developed. The self-renewing potential and differentiation status of novel subpopulations were assessed by sphere-forming ability, cell cycle analysis, immunostaining, qPCR and RNA-Seq. RESULTS: Primary human and mouse oesophageal epithelial cells clonally formed esophagospheres consisting of stratified squamous epithelium. Sphere-forming cells could self-renew and form esophagospheres for over 43 passages in vitro and generated stratified squamous epithelium when transplanted under the kidney capsule of immunodeficient mice. Sphere-forming cells were 10-15-fold enriched among human CD49f(hi)CD24(low) cells and murine CD49f(+)CD24(low)CD71(low) cells compared with the most differentiated cells. Genetic elimination of p63 in mouse and human oesophageal cells dramatically decreased esophagosphere formation and basal gene expression while increasing suprabasal gene expression. CONCLUSIONS: We developed clonogenic and organotypic culture systems for the quantitative analyses of human and mouse oesophageal stem/progenitor cells and identified novel cell surface marker combinations that enrich for these cells. Using this system, we demonstrate that elimination of p63 inhibits self-renewal of human oesophageal stem/progenitor cells. We anticipate that these esophagosphere culture systems will facilitate studies of oesophageal stem cell biology and may prove useful for ex vivo expansion of human oesophageal stem cells.

Quantitative proteomic analysis reveals concurrent RNA-protein interactions and identifies new RNA-binding proteins in Saccharomyces cerevisiae.

A growing body of evidence supports the existence of an extensive network of RNA-binding proteins (RBPs) whose combinatorial binding affects the post-transcriptional fate of every mRNA in the cell-yet we still do not have a complete understanding of which proteins bind to mRNA, which of these bind concurrently, and when and where in the cell they bind. We describe here a method to identify the proteins that bind to RNA concurrently with an RBP of interest, using quantitative mass spectrometry combined with RNase treatment of affinity-purified RNA-protein complexes. We applied this method to the known RBPs Pab1, Nab2, and Puf3. Our method significantly enriched for known RBPs and is a clear improvement upon previous approaches in yeast. Our data reveal that some reported protein-protein interactions may instead reflect simultaneous binding to shared RNA targets. We also discovered more than 100 candidate RBPs, and we independently confirmed that 77% (23/30) bind directly to RNA. The previously recognized functions of the confirmed novel RBPs were remarkably diverse, and we mapped the RNA-binding region of one of these proteins, the transcriptional coactivator Mbf1, to a region distinct from its DNA-binding domain. Our results also provided new insights into the roles of Nab2 and Puf3 in post-transcriptional regulation by identifying other RBPs that bind simultaneously to the same mRNAs. While existing methods can identify sets of RBPs that interact with common RNA targets, our approach can determine which of those interactions are concurrent-a crucial distinction for understanding post-transcriptional regulation.

Improved discovery of molecular interactions in genome-scale data with adaptive model-based normalization.

BACKGROUND: High throughput molecular-interaction studies using immunoprecipitations (IP) or affinity purifications are powerful and widely used in biology research. One of many important applications of this method is to identify the set of RNAs that interact with a particular RNA-binding protein (RBP). Here, the unique statistical challenge presented is to delineate a specific set of RNAs that are enriched in one sample relative to another, typically a specific IP compared to a non-specific control to model background. The choice of normalization procedure critically impacts the number of RNAs that will be identified as interacting with an RBP at a given significance threshold - yet existing normalization methods make assumptions that are often fundamentally inaccurate when applied to IP enrichment data. METHODS: In this paper, we present a new normalization methodology that is specifically designed for identifying enriched RNA or DNA sequences in an IP. The normalization (called adaptive or AD normalization) uses a basic model of the IP experiment and is not a variant of mean, quantile, or other methodology previously proposed. The approach is evaluated statistically and tested with simulated and empirical data. RESULTS AND CONCLUSIONS: The adaptive (AD) normalization method results in a greatly increased range in the number of enriched RNAs identified, fewer false positives, and overall better concordance with independent biological evidence, for the RBPs we analyzed, compared to median normalization. The approach is also applicable to the study of pairwise RNA, DNA and protein interactions such as the analysis of transcription factors via chromatin immunoprecipitation (ChIP) or any other experiments where samples from two conditions, one of which contains an enriched subset of the other, are studied.

Whi3, an S. cerevisiae RNA-binding protein, is a component of stress granules that regulates levels of its target mRNAs.

RNA binding proteins (RBPs) are vital to the regulation of mRNA transcripts, and can alter mRNA localization, degradation, translation, and storage. Whi3 was originally identified in a screen for small cell size mutants, and has since been characterized as an RBP. The identification of Whi3-interacting mRNAs involved in mediating cellular responses to stress suggested that Whi3 might be involved in stress-responsive RNA processing. We show that Whi3 localizes to stress granules in response to glucose deprivation or heat shock. The kinetics and pattern of Whi3 localization in response to a range of temperatures were subtly but distinctly different from those of known components of RNA processing granules. Deletion of Whi3 resulted in an increase in the relative abundance of Whi3 target RNAs, either in the presence or absence of heat shock. Increased levels of the CLN3 mRNA in whi3Δ cells may explain their decreased cell size. Another mRNA target of Whi3 encodes the zinc-responsive transcription factor Zap1, suggesting a role for Whi3 in response to zinc stress. Indeed, we found that whi3Δ cells have enhanced sensitivity to zinc toxicity. Together our results suggest an expanded model for Whi3 function: in addition to its role as a regulator of the cell cycle, Whi3 may have a role in stress-dependent RNA processing and responses to a variety of stress conditions.

Proteome-wide search reveals unexpected RNA-binding proteins in Saccharomyces cerevisiae.

The vast landscape of RNA-protein interactions at the heart of post-transcriptional regulation remains largely unexplored. Indeed it is likely that, even in yeast, a substantial fraction of the regulatory RNA-binding proteins (RBPs) remain to be discovered. Systematic experimental methods can play a key role in discovering these RBPs--most of the known yeast RBPs lack RNA-binding domains that might enable this activity to be predicted. We describe here a proteome-wide approach to identify RNA-protein interactions based on in vitro binding of RNA samples to yeast protein microarrays that represent over 80% of the yeast proteome. We used this procedure to screen for novel RBPs and RNA-protein interactions. A complementary mass spectrometry technique also identified proteins that associate with yeast mRNAs. Both the protein microarray and mass spectrometry methods successfully identify previously annotated RBPs, suggesting that other proteins identified in these assays might be novel RBPs. Of 35 putative novel RBPs identified by either or both of these methods, 12, including 75% of the eight most highly-ranked candidates, reproducibly associated with specific cellular RNAs. Surprisingly, most of the 12 newly discovered RBPs were enzymes. Functional characteristics of the RNA targets of some of the novel RBPs suggest coordinated post-transcriptional regulation of subunits of protein complexes and a possible link between mRNA trafficking and vesicle transport. Our results suggest that many more RBPs still remain to be identified and provide a set of candidates for further investigation.

Influence of physicians' management and communication ability on patients' persistence with antihypertensive medication.

BACKGROUND: Less than 75% of people prescribed antihypertensive medication are still using treatment after 6 months. Physicians determine treatment, educate patients, manage side effects, and influence patient knowledge and motivation. Although physician communication ability likely influences persistence, little is known about the importance of medical management skills, even though these abilities can be enhanced through educational and practice interventions. The purpose of this study was to determine whether a physician's medical management and communication ability influence persistence with antihypertensive treatment. METHODS: This was a population-based study of 13,205 hypertensive patients who started antihypertensive medication prescribed by a cohort of 645 physicians entering practice in Quebec, Canada, between 1993 and 2007. Medical Council of Canada licensing examination scores were used to assess medical management and communication ability. Population-based prescription and medical services databases were used to assess starting therapy, treatment changes, comorbidity, and persistence with antihypertensive treatment in the first 6 months. RESULTS: Within 6 months after starting treatment, 2926 patients (22.2%) had discontinued all antihypertensive medication. The risk of nonpersistence was reduced for patients who were treated by physicians with better medical management (odds ratio per 2-SD increase in score, 0.74; 95% confidence interval, 0.63-0.87) and communication (0.88; 0.78-1.00) ability and with early therapy changes (odds ratio, 0.45; 95% confidence interval, 0.37-0.54), more follow-up visits, and nondiuretics as the initial choice of therapy. Medical management ability was responsible for preventing 15.8% (95% confidence interval, 7.5%-23.3%) of nonpersistence. CONCLUSION: Better clinical decision-making and data collection skills and early modifications in therapy improve persistence with antihypertensive therapy.

Doctor scores on national qualifying examinations predict quality of care in future practice.

OBJECTIVES: This study aimed to determine if national licensing examinations that measure medical knowledge (QE1) and clinical skills (QE2) predict the quality of care delivered by doctors in future practice. METHODS: Cohorts of doctors who took the Medical Council of Canada Qualifying Examinations Part I (QE1) and Part II (QE2) between 1993 and 1996 and subsequently entered practice in Ontario, Canada (n = 2420) were followed for their first 7-10 years in practice. The 208 of these doctors who were randomly selected for peer assessment of quality of care were studied. Main outcome measures included quality of care (acceptable/unacceptable) as assessed by doctor peer-examiners using a structured chart review and interview. Multivariate logistic regression was used to determine if qualifying examination scores predicted the outcome of the peer assessments while controlling for age, sex, training and specialty, and if the addition of the QE2 scores provided additional prediction of quality of care. RESULTS: Fifteen (7.2%) of the 208 doctors assessed were considered to provide unacceptable quality of care. Doctors in the bottom quartile of QE1 scores had a greater than three-fold increase in the risk of an unacceptable quality-of-care assessment outcome (odds ratio [OR] 3.41, 95% confidence interval [CI] 1.14-10.22). Doctors in the bottom quartile of QE2 scores were also at higher risk of being assessed as providing unacceptable quality of care (OR 4.24, 95% CI 1.32-13.61). However, QE2 results provided no significant improvement in predicting peer assessment results over QE1 results (likelihood ratio test: chi(2) = 3.21, P-value((1 d.f.)) = 0.07). CONCLUSIONS: Doctor scores on qualifying examinations are significant predictors of quality-of-care problems based on regulatory, practice-based peer assessment.

Factors affecting physician performance: implications for performance improvement and governance.

BACKGROUND: A physician's personal and professional characteristics constitute only one, and not necessarily the most important, determining factor of clinical performance. Our study assessed how physician, organizational and systemic factors affect family physicians' performance. METHOD: Our study examined 532 family practitioners who were randomly selected for peer assessment by the College of Physicians and Surgeons of Ontario. A series of multivariate regression analyses examined the impact of physician factors (e.g., demographics, certification) on performance scores in five clinical areas: acute care, chronic conditions, continuity of care and referrals, well care and records. A second series of regressions examined the simultaneous effects of physician, organizational (e.g., practice volume, hours worked, solo practice) and systemic factors (e.g., northern practice location, community size, physician-to-population ratio). RESULTS: OUR STUDY HAD THREE KEY FINDINGS: (a) physician factors significantly influence performance but do not appear to be nearly as important as previously thought; (b) organizational and systemic factors have significant effects on performance after the effects of physician factors are controlled; and (c) physician, organizational and systemic factors have varying effects across different dimensions of clinical performance. CONCLUSIONS: We discuss the implications of our results for performance improvement and physician governance insofar as both need to consider the broader environmental context of medical practice.

Predicting doctor performance outcomes of curriculum interventions: problem-based learning and continuing competence.

CONTEXT: Problem-based learning (PBL) is an educational strategy designed to enhance self-assessment, self-directed learning and lifelong learning. The present study examines a peer review programme to determine whether the impact of PBL on continuing competence can be detected in practice. OBJECTIVES: This study aimed to establish whether McMaster graduates who graduated between 1972 and 1991 were any less likely to be identified as having issues of competence by a systematic peer review programme than graduates of other Ontario medical schools. METHODS: We identified a total of 1166 doctors who had graduated after 1972 and had completed a mandated peer review programme. Of these, 108 had graduated from McMaster and 857 from other Canadian schools. School of graduation was cross-tabulated against peer rating. A secondary analysis examined predictors of ratings using multiple regression. RESULTS: We found that 4% of McMaster graduates and 5% of other graduates were deemed to demonstrate cause for concern or serious concern, and that 24% of McMaster doctors and 28% of other doctors were rated as excellent. These differences were not significant. Multiple regression indicated that certification by family medicine or a specialty, female gender and younger age were all predictors of practice outcomes, but school of graduation was not. CONCLUSIONS: There is no evidence from this study that PBL graduates are better able to maintain competence than graduates of conventional schools. The study highlights potential problems in attempting to link undergraduate educational interventions to doctor performance outcomes.

Physician scores on a national clinical skills examination as predictors of complaints to medical regulatory authorities.

CONTEXT: Poor patient-physician communication increases the risk of patient complaints and malpractice claims. To address this problem, licensure assessment has been reformed in Canada and the United States, including a national standardized assessment of patient-physician communication and clinical history taking and examination skills. OBJECTIVE: To assess whether patient-physician communication examination scores in the clinical skills examination predicted future complaints in medical practice. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of all 3424 physicians taking the Medical Council of Canada clinical skills examination between 1993 and 1996 who were licensed to practice in Ontario and/or Quebec. Participants were followed up until 2005, including the first 2 to 12 years of practice. MAIN OUTCOME MEASURE: Patient complaints against study physicians that were filed with medical regulatory authorities in Ontario or Quebec and retained after investigation. Multivariate Poisson regression was used to estimate the relationship between complaint rate and scores on the clinical skills examination and traditional written examination. Scores are based on a standardized mean (SD) of 500 (100). RESULTS: Overall, 1116 complaints were filed for 3424 physicians, and 696 complaints were retained after investigation. Of the physicians, 17.1% had at least 1 retained complaint, of which 81.9% were for communication or quality-of-care problems. Patient-physician communication scores for study physicians ranged from 31 to 723 (mean [SD], 510.9 [91.1]). A 2-SD decrease in communication score was associated with 1.17 more retained complaints per 100 physicians per year (relative risk [RR], 1.38; 95% confidence interval [CI], 1.18-1.61) and 1.20 more communication complaints per 100 practice-years (RR, 1.43; 95% CI, 1.15-1.77). After adjusting for the predictive ability of the clinical decision-making score in the traditional written examination, the patient-physician communication score in the clinical skills examination remained significantly predictive of retained complaints (likelihood ratio test, P < .001), with scores in the bottom quartile explaining an additional 9.2% (95% CI, 4.7%-13.1%) of complaints. CONCLUSION: Scores achieved in patient-physician communication and clinical decision making on a national licensing examination predicted complaints to medical regulatory authorities.

A performance-based conception of competence is changing the regulation of physicians' professional behavior.

It is the obligation of a profession to articulate the special meaning of competence in its field and to foster the good performance of its practitioners through education and discipline. External societal demands for increased accountability, and internal pressures for greater use of measurements of the processes and outcomes of clinical performance, are forcing the medical profession to reevaluate its view of competence and to change the way the profession "manages" the competence of its members. Traditionally, and predicated on the notion of "once in, good for life," medical education has focused on assuring the competence of trainees as they first enter independent professional life. In parallel, professional regulatory authorities have concentrated on apprehending the "false-positives" of the educational system. But viewed from a performance orientation, competence reflects situational relationships among doctors, their patients, and the systems in which they perform and, thus, is only partly dependent on the attributes of individual actors. This shift in thinking has major implications for the practice of medicine, particularly for the process of maintaining and improving performance. In jurisdictions throughout the world, recognition of the need for systematic and accountable ongoing education for practicing doctors is growing. This educational need should not be seen as a mark of weakness or failure but, rather, as the natural consequence of engagement in challenging practice. "Ars longa, vita breva." The profession must address the complex issues of education-in-practice with the same determination and creativity that it previously applied to education at entry to practice.

Physician-patient encounters: the structure of performance in family and general office practice.

INTRODUCTION: The College of Physicians and Surgeons of Ontario, the regulatory authority for physicians in Ontario, Canada, conducts peer assessments of physicians' practices as part of a broad quality assurance program. Outcomes are summarized as a single score and there is no differentiation between performance in various aspects of care. In this study we test the hypothesis that physician performance is multidimensional and that dimensions can be defined in terms of physician-patient encounters. METHODS: Peer assessment data from 532 randomly selected family practitioners were analyzed using factor analysis to assess the dimensional structure of performance. Content validity was confirmed through consultation sessions with 130 physicians. Multiple-item measures were constructed for each dimension and reliability calculated. Analysis of variance determined the extent to which multiple-item measure scores would vary across peer assessment outcomes. RESULTS: Six performance dimensions were confirmed: acute care, chronic conditions, continuity of care and referrals, well care and health maintenance, psychosocial care, and patient records. DISCUSSION: Physician performance is multidimensional, including types of physician-patient encounters and variation across dimensions, as demonstrated by individual practice. A conceptual framework for multidimensional performance may inform the design of meaningful evaluation and educational recommendations to meet the individual performance of practicing physicians.

Effectiveness of an enhanced peer assessment program: introducing education into regulatory assessment.

INTRODUCTION: The College of Physicians and Surgeons of Ontario developed an enhanced peer assessment (EPA), the goal of which was to provide participating physicians educational value by helping them identify specific learning needs and aligning the assessment process with the principles of continuing education and professional development. In this article, we examine the educational value of the EPA and whether physicians will change their practice as a result of the recommendations received during the assessment. METHODS: A group of 41 randomly selected physicians (23 general or family practitioners, 7 obstetrician-gynecologists, and 11 general surgeons) agreed to participate in the EPA pilot. Nine experienced peer assessors were trained in the principles of knowledge translation and the use of practice resources (tool kits) and clinical practice guidelines. The EPA was evaluated through the use of a postassessment questionnaire and focus groups. RESULTS: The physicians felt that the EPA was fair and educationally valuable. Most focus group participants indicated that they implemented recommendations made by the assessor and made changes to some aspect of their practice. The physicians' suggestions for improvement included expanding the assessment beyond the current medical record review and interview format (eg, to include multisource feedback), having assessments occur at regular intervals (eg, every 5 to 10 years), and improving the administrative process by which physicians apply for educational credit for EPA activities. CONCLUSIONS: The EPA pilot study has demonstrated that providing detailed individualized feedback and optimizing the one-to-one interaction between assessors and physicians is a promising method for changing physician behavior. The college has started the process of aligning all its peer assessments with the principles of continuing professional development outlined in the EPA model.