Publications by authors named "Kathleen F Kerr"

98 Publications

More scanning, but not zooming, is associated with diagnostic accuracy in evaluating digital breast pathology slides.

J Vis 2021 Oct;21(11)

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Diagnoses of medical images can invite strikingly diverse strategies for image navigation and visual search. In computed tomography screening for lung nodules, distinct strategies, termed scanning and drilling, relate to both radiologists' clinical experience and accuracy in lesion detection. Here, we examined associations between search patterns and accuracy for pathologists (N = 92) interpreting a diverse set of breast biopsy images. While changes in depth in volumetric images reveal new structures through movement in the z-plane, in digital pathology changes in depth are associated with increased magnification. Thus, "drilling" in radiology may be more appropriately termed "zooming" in pathology. We monitored eye-movements and navigation through digital pathology slides to derive metrics of how quickly the pathologists moved through XY (scanning) and Z (zooming) space. Prior research on eye-movements in depth has categorized clinicians as either "scanners" or "drillers." In contrast, we found that there was no reliable association between a clinician's tendency to scan or zoom while examining digital pathology slides. Thus, in the current work we treated scanning and zooming as continuous predictors rather than categorizing as either a "scanner" or "zoomer." In contrast to prior work in volumetric chest images, we found significant associations between accuracy and scanning rate but not zooming rate. These findings suggest fundamental differences in the relative value of information types and review behaviors across two image formats. Our data suggest that pathologists gather critical information by scanning on a given plane of depth, whereas radiologists drill through depth to interrogate critical features.
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http://dx.doi.org/10.1167/jov.21.11.7DOI Listing
October 2021

Recalibration Methods for Improved Clinical Utility of Risk Scores.

Med Decis Making 2021 Oct 4:272989X211044697. Epub 2021 Oct 4.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Background: An established risk model may demonstrate miscalibration, meaning predicted risks do not accurately capture event rates. In some instances, investigators can identify and address the cause of miscalibration. In other circumstances, it may be appropriate to recalibrate the risk model. Existing recalibration methods do not account for settings in which the risk score will be used for risk-based clinical decision making.

Methods: We propose 2 new methods for risk model recalibration when the intended purpose of the risk model is to prescribe an intervention to high-risk individuals. Our measure of risk model clinical utility is standardized net benefit. The first method is a weighted strategy that prioritizes good calibration at or around the critical risk threshold. The second method uses constrained optimization to produce a recalibrated risk model with maximum possible net benefit, thereby prioritizing good calibration around the critical risk threshold. We also propose a graphical tool for assessing the potential for recalibration to improve the net benefit of a risk model. We illustrate these methods by recalibrating the American College of Cardiology (ACC)-American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk score within the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.

Results: New methods are implemented in the R package . Recalibrating the ACC-AHA-ASCVD risk score for a MESA subcohort results in higher estimated net benefit using the proposed methods compared with existing methods, with improved calibration in the most clinically impactful regions of risk.

Conclusion: The proposed methods target good calibration for critical risks and can improve the net benefit of a risk model. We recommend constrained optimization when the risk model net benefit is paramount. The weighted approach can be considered when good calibration over an interval of risks is important.
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http://dx.doi.org/10.1177/0272989X211044697DOI Listing
October 2021

Characterization of multiple diagnostic terms in melanocytic skin lesion pathology reports.

J Cutan Pathol 2021 Sep 6. Epub 2021 Sep 6.

Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Background: Histopathologically ambiguous melanocytic lesions lead some pathologists to list multiple diagnostic considerations in the pathology report. The frequency and circumstance of multiple diagnostic considerations remain poorly characterized.

Methods: Two hundred and forty skin biopsy samples were interpreted by 187 pathologists (8976 independent diagnoses) and classified according to a diagnostic/treatment stratification (MPATH-Dx).

Results: Multiple diagnoses in different MPATH-Dx classes were used in n = 1320 (14.7%) interpretations, with 97% of pathologists and 91% of cases having at least one such interpretation. Multiple diagnoses were more common for intermediate risk lesions and are associated with greater subjective difficulty and lower confidence. We estimate that 6% of pathology reports for melanocytic lesions in the United States contain two diagnoses of different MPATH-Dx prognostic classes, and 2% of cases are given two diagnoses with significant treatment implications.

Conclusions: Difficult melanocytic diagnoses in skin may necessitate multiple diagnostic considerations; however, as patients increasingly access their health records and retrieve pathology reports (as mandated by US law), uncertainty should be expressed unambiguously.
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http://dx.doi.org/10.1111/cup.14126DOI Listing
September 2021

Histopathologic synoptic reporting of invasive melanoma: How reliable are the data?

Cancer 2021 Sep 4;127(17):3125-3136. Epub 2021 May 4.

Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Background: Synoptic reporting is recommended by many guideline committees to encourage the thorough histologic documentation necessary for optimal management of patients with melanoma.

Methods: One hundred fifty-one pathologists from 40 US states interpreted 41 invasive melanoma cases. For each synoptic reporting factor, the authors identified cases with "complete agreement" (all participants recorded the same value) versus any disagreement. Pairwise agreement was calculated for each case as the proportion of pairs of responses that agreed, where paired responses were generated by the comparison of each reviewer's response with all others.

Results: There was complete agreement among all reviewers for 22 of the 41 cases (54%) on Breslow thickness dichotomized at 0.8 mm, with pairwise agreement ranging from 49% to 100% across the 41 cases. There was complete agreement for "no ulceration" in 24 of the 41 cases (59%), with pairwise agreement ranging from 42% to 100%. Tumor transected at base had complete agreement for 26 of the 41 cases (63%), with pairwise agreement ranging from 31% to 100%. Mitotic rate, categorized as 0/mm , 1/mm , or 2/mm , had complete agreement for 17 of the 41 cases (41%), with pairwise agreement ranging from 36% to 100%. Regression saw complete agreement for 14 of 41 cases (34%), with pairwise agreement ranging from 40% to 100%. Lymphovascular invasion, perineural invasion, and microscopic satellites were rarely reported as present. Respectively, these prognostic factors had complete agreement for 32 (78%), 37 (90%), and 18 (44%) of the 41 cases, and the ranges of pairwise agreement were 47% to 100%, 70% to 100%, and 53% to 100%, respectively.

Conclusions: These findings alert pathologists and clinicians to the problem of interobserver variability in recording critical prognostic factors.

Lay Summary: This study addresses variability in the assessment and reporting of critical characteristics of invasive melanomas that are used by clinicians to guide patient care. The authors characterize the diagnostic variability among pathologists and their reporting methods in light of recently updated national guidelines. Results demonstrate considerable variability in the diagnostic reporting of melanoma with regard to the following: Breslow thickness, mitotic rate, ulceration, regression, and microscopic satellites. This work serves to alert pathologists and clinicians to the existence of variability in reporting these prognostic factors.
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http://dx.doi.org/10.1002/cncr.33612DOI Listing
September 2021

Combining biomarkers by maximizing the true positive rate for a fixed false positive rate.

Biom J 2021 Aug 19;63(6):1223-1240. Epub 2021 Apr 19.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Biomarkers abound in many areas of clinical research, and often investigators are interested in combining them for diagnosis, prognosis, or screening. In many applications, the true positive rate (TPR) for a biomarker combination at a prespecified, clinically acceptable false positive rate (FPR) is the most relevant measure of predictive capacity. We propose a distribution-free method for constructing biomarker combinations by maximizing the TPR while constraining the FPR. Theoretical results demonstrate desirable properties of biomarker combinations produced by the new method. In simulations, the biomarker combination provided by our method demonstrated improved operating characteristics in a variety of scenarios when compared with alternative methods for constructing biomarker combinations. Thus, use of our method could lead to the development of better biomarker combinations, increasing the likelihood of clinical adoption.
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http://dx.doi.org/10.1002/bimj.202000210DOI Listing
August 2021

Epigenome-wide analysis of long-term air pollution exposure and DNA methylation in monocytes: results from the Multi-Ethnic Study of Atherosclerosis.

Epigenetics 2021 Apr 5:1-17. Epub 2021 Apr 5.

Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and -gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM) and oxides of nitrogen (NO) were estimated at participants' homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and -gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near , and , respectively) were associated with PM. The DMRs on chromosomes 5 and 6 also associated with NO. The DMR on chromosome 5 had the smallest p-value for both PM (p = 1.4×10) and NO (p = 7.7×10). Three differentially methylated CpGs were identified for PM, and cg05926640 (near ) had the smallest p-value (p = 5.6×10). NO significantly associated with cg11756214 within (p = 5.6×10). Several differentially methylated signals were also associated with -gene expression. The DMR located on chromosome 7 was associated with the expression of , and . The DMRs located on chromosomes 5 and 16 were associated with expression of and , respectively. The CpG cg05926640 was associated with expression of , and . We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.
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http://dx.doi.org/10.1080/15592294.2021.1900028DOI Listing
April 2021

Gastrointestinal Cancer Survival and Radiation Exposure among Atomic Bomb Survivors: The Life Span Study.

Cancer Epidemiol Biomarkers Prev 2021 02 16;30(2):412-418. Epub 2020 Nov 16.

Department of Epidemiology, University of Washington, Seattle, Washington.

Background: Radiation exposure is an established risk factor for the development of several forms of cancer, including gastrointestinal cancers. However, few studies have investigated the relationship between prediagnostic radiation exposure and survival after cancer diagnosis.

Methods: Participants in the Life Span Study (LSS) of atomic bomb survivors who were diagnosed with a first primary invasive stomach, colon, or rectal cancer between 1958 and 2009 were followed for mortality during 1958-2014. Cox regression models were used to calculate HRs and 95% confidence intervals (CI) for associations of radiation dose from atomic bomb exposure with survival (cancer-specific and overall) after cancer diagnosis. Analyses were adjusted for city of primary exposure, sex, age at diagnosis, and year of diagnosis.

Results: We identified 7,728 eligible patients with cancer for analysis. We observed no statistically significant associations between radiation dose and cancer-specific survival among LSS participants with a gastrointestinal cancer. Higher radiation doses (≥1 Gy) were suggestively, but not significantly, associated with modestly poorer cancer-specific survival for colon cancer only (HR, 1.38; 95% CI, 0.90-2.12), and were associated with poorer overall survival regardless of cancer site.

Conclusions: Although radiation exposure is associated with increased risk of gastrointestinal cancer incidence and mortality, study results are inconclusive about an association between prediagnostic radiation exposure and survival after gastrointestinal cancer diagnosis.

Impact: Radiation exposure from the atomic bomb before gastrointestinal cancer diagnosis was not associated with cancer survival, but should be evaluated in relation to survival for other cancer types.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1239DOI Listing
February 2021

Pathology Trainees' Experience and Attitudes on Use of Digital Whole Slide Images.

Acad Pathol 2020 Jan-Dec;7:2374289520951922. Epub 2020 Sep 30.

Department of Pathology and Laboratory Medicine, University of Vermont, Larner College of Medicine, Burlington, VT, USA.

Digital whole slide images are Food and Drug Administration approved for clinical diagnostic use in pathology; however, integration is nascent. Trainees from 9 pathology training programs completed an online survey to ascertain attitudes toward and experiences with whole slide images for pathological interpretations. Respondents (n = 76) reported attending 63 unique medical schools (45 United States, 18 international). While 63% reported medical school exposure to whole slide images, most reported ≤ 5 hours. Those who began training more recently were more likely to report at least some exposure to digital whole slide image training in medical school compared to those who began training earlier: 75% of respondents beginning training in 2017 or 2018 reported exposure to whole slide images compared to 54% for trainees beginning earlier. Trainees exposed to whole slide images in medical school were more likely to agree they were comfortable using whole slide images for interpretation compared to those not exposed (29% vs 12%; = .06). Most trainees agreed that accurate diagnoses can be made using whole slide images for primary diagnosis (92%; 95% CI: 86-98) and that whole slide images are useful for obtaining second opinions (93%; 95% CI: 88-99). Trainees reporting whole slide image experience during training, compared to those with no experience, were more likely to agree they would use whole slide images in 5 years for primary diagnosis (64% vs 50%; = .3) and second opinions (86% vs 76%; = .4). In conclusion, although exposure to whole slide images in medical school has increased, overall exposure is limited. Positive attitudes toward future whole slide image diagnostic use were associated with exposure to this technology during medical training. Curricular integration may promote adoption.
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http://dx.doi.org/10.1177/2374289520951922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545516PMC
September 2020

BioPETsurv: Methodology and open source software to evaluate biomarkers for prognostic enrichment of time-to-event clinical trials.

PLoS One 2020 18;15(9):e0239486. Epub 2020 Sep 18.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Biomarkers can be used to enrich a clinical trial for patients at higher risk for an outcome, a strategy termed "prognostic enrichment." Methodology is needed to evaluate biomarkers for prognostic enrichment of trials with time-to-event endpoints such as survival. Key considerations when considering prognostic enrichment include: clinical trial sample size; the number of patients one must screen to enroll the trial; and total patient screening costs and total per-patient trial costs. The Biomarker Prognostic Enrichment Tool for Survival Outcomes (BioPETsurv) is a suite of methods for estimating these elements to evaluate a prognostic enrichment biomarker and/or plan a prognostically enriched clinical trial with a time-to-event primary endpoint. BioPETsurv allows investigators to analyze data on a candidate biomarker and potentially censored survival times. Alternatively, BioPETsurv can simulate data to match a particular clinical setting. BioPETsurv's data simulator enables investigators to explore the potential utility of a prognostic enrichment biomarker for their clinical setting. Results demonstrate that both modestly prognostic and strongly prognostic biomarkers can improve trial metrics such as reducing sample size or trial costs. In addition to the quantitative analysis provided by BioPETsurv, investigators should consider the generalizability of trial results and evaluate the ethics of trial eligibility criteria. BioPETsurv is freely available as a package for the R statistical computing platform, and as a webtool at www.prognosticenrichment.com/surv.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239486PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500596PMC
November 2020

Terminology for melanocytic skin lesions and the MPATH-Dx classification schema: A survey of dermatopathologists.

J Cutan Pathol 2021 Jun 6;48(6):733-738. Epub 2020 Nov 6.

Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Background: Diagnostic terms used in histopathology reports of cutaneous melanocytic lesions are not standardized. We describe dermatopathologists' views regarding diverse diagnostic terminology and the utility of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) for categorizing melanocytic lesions.

Methods: July 2018-2019 survey of board-certified and/or fellowship-trained dermatopathologists with experience interpreting melanocytic lesions.

Results: Among 160 participants, 99% reported witnessing different terminology being used for the same melanocytic lesion. Most viewed diverse terminology as confusing to primary care physicians (98%), frustrating to pathologists (83%), requiring more of their time as a consultant (64%), and providing necessary clinical information (52%). Most perceived that adoption of the MPATH-Dx would: improve communication with other pathologists and treating physicians (87%), generally be a change for the better (80%), improve patient care (79%), be acceptable to clinical colleagues (68%), save time in pathology report documentation (53%), and protect from malpractice (51%).

Conclusions: Most dermatopathologists view diverse terminology as contributing to miscommunication with clinicians and patients, adversely impacting patient care. They view the MPATH-Dx as a promising tool to standardize terminology and improve communication. The MPATH-Dx may be a useful supplement to conventional pathology reports. Further revision and refinement are necessary for widespread clinical use.
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http://dx.doi.org/10.1111/cup.13873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960566PMC
June 2021

Developing biomarker combinations in multicenter studies via direct maximization and penalization.

Stat Med 2020 10 13;39(24):3412-3426. Epub 2020 Aug 13.

Department of Biostatistics, University of Washington, Seattle, Washington, USA.

Motivated by a study of acute kidney injury, we consider the setting of biomarker studies involving patients at multiple centers where the goal is to develop a biomarker combination for diagnosis, prognosis, or screening. As biomarker studies become larger, this type of data structure will be encountered more frequently. In the presence of multiple centers, one way to assess the predictive capacity of a given combination is to consider the center-adjusted area under the receiver operating characteristic curve (aAUC), a summary of the ability of the combination to discriminate between cases and controls in each center. Rather than using a general method, such as logistic regression, to construct the biomarker combination, we propose directly maximizing the aAUC. Furthermore, it may be desirable to have a biomarker combination with similar performance across centers. To that end, we allow for penalization of the variability in the center-specific AUCs. We demonstrate desirable asymptotic properties of the resulting combinations. Simulations provide small-sample evidence that maximizing the aAUC can lead to combinations with improved performance. We also use simulated data to illustrate the utility of constructing combinations by maximizing the aAUC while penalizing variability. Finally, we apply these methods to data from the study of acute kidney injury.
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http://dx.doi.org/10.1002/sim.8673DOI Listing
October 2020

Excess Patient Visits for Cough and Pulmonary Disease at a Large US Health System in the Months Prior to the COVID-19 Pandemic: Time-Series Analysis.

J Med Internet Res 2020 09 10;22(9):e21562. Epub 2020 Sep 10.

Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States.

Background: Accurately assessing the regional activity of diseases such as COVID-19 is important in guiding public health interventions. Leveraging electronic health records (EHRs) to monitor outpatient clinical encounters may lead to the identification of emerging outbreaks.

Objective: The aim of this study is to investigate whether excess visits where the word "cough" was present in the EHR reason for visit, and hospitalizations with acute respiratory failure were more frequent from December 2019 to February 2020 compared with the preceding 5 years.

Methods: A retrospective observational cohort was identified from a large US health system with 3 hospitals, over 180 clinics, and 2.5 million patient encounters annually. Data from patient encounters from July 1, 2014, to February 29, 2020, were included. Seasonal autoregressive integrated moving average (SARIMA) time-series models were used to evaluate if the observed winter 2019/2020 rates were higher than the forecast 95% prediction intervals. The estimated excess number of visits and hospitalizations in winter 2019/2020 were calculated compared to previous seasons.

Results: The percentage of patients presenting with an EHR reason for visit containing the word "cough" to clinics exceeded the 95% prediction interval the week of December 22, 2019, and was consistently above the 95% prediction interval all 10 weeks through the end of February 2020. Similar trends were noted for emergency department visits and hospitalizations starting December 22, 2019, where observed data exceeded the 95% prediction interval in 6 and 7 of the 10 weeks, respectively. The estimated excess over the 3-month 2019/2020 winter season, obtained by either subtracting the maximum or subtracting the average of the five previous seasons from the current season, was 1.6 or 2.0 excess visits for cough per 1000 outpatient visits, 11.0 or 19.2 excess visits for cough per 1000 emergency department visits, and 21.4 or 39.1 excess visits per 1000 hospitalizations with acute respiratory failure, respectively. The total numbers of excess cases above the 95% predicted forecast interval were 168 cases in the outpatient clinics, 56 cases for the emergency department, and 18 hospitalized with acute respiratory failure.

Conclusions: A significantly higher number of patients with respiratory complaints and diseases starting in late December 2019 and continuing through February 2020 suggests community spread of SARS-CoV-2 prior to established clinical awareness and testing capabilities. This provides a case example of how health system analytics combined with EHR data can provide powerful and agile tools for identifying when future trends in patient populations are outside of the expected ranges.
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http://dx.doi.org/10.2196/21562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485935PMC
September 2020

Malpractice and Patient Safety Concerns.

Am J Clin Pathol 2020 10;154(5):700-707

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.

Objectives: "Assurance behaviors," a type of defensive medicine, involve physicians' utilization of additional patient services to avoid adverse legal outcomes. We aim to compare the use of clinical behaviors (such as ordering additional tests, services, and consultations) due to malpractice concerns with the same behaviors due to patient safety concerns.

Methods: A national sample of dermatopathologists (n = 160) completed an online survey.

Results: Participants reported using one or more of five clinical behaviors due to concerns about medical malpractice (95%) and patient safety (99%). Self-reported use of clinical behaviors due to malpractice concerns and patient safety concerns was compared, including ordering additional immunohistochemistry/molecular tests (71% vs 90%, respectively, P < .0001), recommending additional surgical sampling (78% vs 91%, P < .0001), requesting additional slides (81% vs 95%, P < .0001), obtaining second reviews (78% vs 91%, P < .0001), and adding caveats into reports regarding lesion difficulty (85% vs 89%, P > .05).

Conclusions: Dermatopathologists use many clinical behaviors both as assurance behaviors and due to patient safety concerns, with a higher proportion reporting patient safety concerns as a motivation for specific behaviors.
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http://dx.doi.org/10.1093/ajcp/aqaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553247PMC
October 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Factors associated with use of immunohistochemical markers in the histopathological diagnosis of cutaneous melanocytic lesions.

J Cutan Pathol 2020 Oct 17;47(10):896-902. Epub 2020 Jul 17.

Division of General Internal Medicine and Health Services Research, UCLA David Geffen School of Medicine, Los Angeles, California, USA.

Background: Melanocytic tumors are often challenging and constitute almost one in four skin biopsies. Immunohistochemical (IHC) studies may assist diagnosis; however, indications for their use are not standardized.

Methods: A test set of 240 skin biopsies of melanocytic tumors was examined by 187 pathologists from 10 US states, interpreting 48 cases in Phase I and either 36 or 48 cases in Phase II. Participant and diagnosis characteristics were compared between those who reported they would have ordered, or who would have not ordered IHC on individual cases. Intraobserver analysis examined consistency in the intent to order when pathologists interpreted the same cases on two occasions.

Results: Of 187 participants interpreting 48 cases each, 21 (11%) did not request IHC tests for any case, 85 (45%) requested testing for 1 to 6 cases, and 81 (43%) requested testing for ≥6 cases. Of 240 cases, 229 had at least one participant requesting testing. Only 2 out of 240 cases had more than 50% of participants requesting testing. Increased utilization of testing was associated with younger age of pathologist, board-certification in dermatopathology, low confidence in diagnosis, and lesions in intermediate MPATH-Dx classes 2 to 4. The median intraobserver concordance for requesting tests among 72 participants interpreting the same 48 cases in Phases I and II was 81% (IQR 73%-90%) and the median Kappa statistic was 0.20 (IQR 0.00, 0.39).

Conclusion: Substantial variability exists among pathologists in utilizing IHC.
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http://dx.doi.org/10.1111/cup.13736DOI Listing
October 2020

Dermatopathologists' Experience With and Perceptions of Patient Online Access to Pathologic Test Result Reports.

JAMA Dermatol 2020 03;156(3):320-324

David Geffen School of Medicine, Department of Medicine, University of California, Los Angeles.

Importance: Many patients presently have access to their pathologic test result reports via online patient portals, yet little is known about pathologists' perspective on this topic.

Objective: To examine dermatopathologists' experience and perceptions of patient online access to pathology reports.

Design, Setting, And Participants: A survey of 160 dermatopathologists currently practicing in the United States who are board certified and/or fellowship trained in dermatopathology was conducted between July 15, 2018, and September 23, 2019. Those who reported interpreting skin biopsies of melanocytic lesions within the previous year and expected to continue interpreting them for the next 2 years were included.

Main Outcomes And Measures: Dermatopathologists' demographic and clinical characteristics, experiences with patient online access to pathologic test result reports, potential behaviors and reactions to patient online access to those reports, and effects on patients who read their pathologic test result reports online.

Results: Of the 160 participating dermatopathologists from the 226 eligible for participation (71% response rate), 107 were men (67%); mean (SD) age was 49 (9.7) years (range, 34-77 years). Ninety-one participants (57%) reported that patients have contacted them directly about pathologic test reports they had written. Some participants noted that they would decrease their use of abbreviations and/or specialized terminology (57 [36%]), change the way they describe lesions suspicious for cancer (29 [18%]), and need specialized training in communicating with patients (39 [24%]) if patients were reading their reports. Most respondents perceived that patient understanding would increase (97 [61%]) and the quality of patient-physician communication would increase (98 [61%]) owing to the availability of online reports. Slightly higher proportions perceived increased patient worry (114 [71%]) and confusion (116 [73%]). However, on balance, most participants (114 [71%]) agreed that making pathologic test result reports available to patients online is a good idea.

Conclusions And Relevance: Dermatopathologists in this survey study perceived both positive and negative consequences of patient online access to pathologic test result reports written by the respondents. Most participants believe that making pathologic test result reports available to patients online is a good idea; however, they also report concerns about patient worry and confusion increasing as a result. Further research regarding best practices and the effect on both patients and clinicians is warranted.
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http://dx.doi.org/10.1001/jamadermatol.2019.4194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990839PMC
March 2020

Pathologists' agreement on treatment suggestions for melanocytic skin lesions.

J Am Acad Dermatol 2020 Jun 17;82(6):1435-1444. Epub 2019 Dec 17.

Department of Medicine, University of Washington School of Medicine, Seattle, Washington; Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California. Electronic address:

Background: Although treatment guidelines exist for melanoma in situ and invasive melanoma, guidelines for other melanocytic skin lesions do not exist.

Objective: To examine pathologists' treatment suggestions for a broad spectrum of melanocytic skin lesions and compare them with existing guidelines.

Methods: Pathologists (N = 187) completed a survey and then provided diagnoses and treatment suggestions for 240 melanocytic skin lesions. Physician characteristics associated with treatment suggestions were evaluated with multivariable modeling.

Results: Treatment suggestions were concordant with National Comprehensive Cancer Network guidelines for the majority of cases interpreted as melanoma in situ (73%) and invasive melanoma (86%). Greater variability of treatment suggestions was seen for other lesion types without existing treatment guidelines. Characteristics associated with provision of treatment suggestions discordant with National Comprehensive Cancer Network guidelines were low caseloads (invasive melanoma), lack of fellowship training or board certification (melanoma in situ), and more than 10 years of experience (invasive melanoma and melanoma in situ).

Limitations: Pathologists could not perform immunohistochemical staining or other diagnostic tests; only 1 glass side was provided per biopsy case.

Conclusions: Pathologists' treatment suggestions vary significantly for melanocytic lesions, with lower variability for lesion types with national guidelines. Results suggest the need for standardization of treatment guidelines for all melanocytic lesion types.
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http://dx.doi.org/10.1016/j.jaad.2019.12.020DOI Listing
June 2020

Developing Biomarker Panels to Predict Progression of Acute Kidney Injury After Cardiac Surgery.

Kidney Int Rep 2019 Dec 30;4(12):1677-1688. Epub 2019 Aug 30.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Introduction: Acute kidney injury (AKI) is a frequent complication of cardiac surgery, but only a fraction of cardiac surgery patients that experience postoperative AKI have progression to more severe stages. Biomarkers that can distinguish patients that will experience progression of AKI are potentially useful for clinical care and/or the development of therapies.

Methods: Data come from a prospective cohort study of cardiac surgery patients; the analytic dataset contained data from 354 cardiac surgery patients meeting criteria for AKI following surgery. Candidate predictors were 38 biomarkers of kidney function, insult, or injury measured at the time of AKI diagnosis. The outcome was AKI progression, defined as worsening of AKI Network stage. We investigated combining biomarkers with Bayesian model averaging (BMA) and random forests of classification trees, with and without center transformation. For both approaches, we used resampling-based methods to avoid optimistic bias in our assessment of model performance.

Results: BMA yielded a combination of 3 biomarkers and an optimism-corrected estimated area under the receiver operating characteristic curve (AUC) of 0.75 (95% confidence interval [CI]: 0.68, 0.82). The random forests approach, which nominally uses all biomarkers, had an estimated AUC of 0.74 (95% CI: 0.66, 0.82). A second application of random forests applied to biomarker values after a center-specific transformation had an estimated AUC of 0.80 (95% CI: 0.72, 0.88).

Conclusion: These findings suggest that the application of advanced statistical techniques to combine biomarkers offers only modest improvements over use of single biomarkers alone. This exemplifies a common experience in biomarker research: combinations of modestly performing biomarkers often also have modest performance.
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http://dx.doi.org/10.1016/j.ekir.2019.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895663PMC
December 2019

Quantifying Donor Effects on Transplant Outcomes Using Kidney Pairs from Deceased Donors.

Clin J Am Soc Nephrol 2019 12 1;14(12):1781-1787. Epub 2019 Nov 1.

Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, Maryland;

Background And Objectives: In kidney transplantation, the relative contribution of donor versus other factors on clinical outcomes is unknown. We sought to quantify overall donor effects on transplant outcomes for kidney donations from deceased donors.

Design, Setting, Participants, & Measurements: For paired donations from deceased donors resulting in transplants to different recipients, the magnitude of donor effects can be quantified by examining the excess of concordant outcomes within kidney pairs beyond chance concordance. Using data from the Organ Procurement and Transplantation Network between the years 2013 and 2017, we examined concordance measures for delayed graft function, death-censored 1-year graft failure, and death-censored 3-year graft failure. The concordance measures were excess relative risk, excess absolute risk, and the fixation index (where zero is no concordance and one is perfect concordance). We further examined concordance in strata of kidneys with similar values of the Kidney Donor Profile Index, a common metric of organ quality.

Results: If the transplant of the kidney mate resulted in delayed graft function, risk for delayed graft function was 19% higher (95% confidence interval [95% CI], 18% to 20%), or 1.76-fold higher (95% CI, 1.73- to 1.80-fold), than baseline. If a kidney graft failed within 1 year, then the kidney mate's risk of failure was 6% higher (95% CI, 4% to 9%), or 2.85-fold higher (95% CI, 2.25- to 3.48-fold), than baseline. For 3-year graft failure, the excess absolute risk was 7% (95% CI, 4% to 10%) but excess relative risk was smaller, 1.91-fold (95% CI, 1.56- to 2.28-fold). Fixation indices were 0.25 for delayed graft function (95% CI, 0.24 to 0.27), 0.07 for 1-year graft failure (95% CI, 0.04 to 0.09), and 0.07 for 3-year graft failure (95% CI, 0.04 to 0.10). Results were similar in strata of kidneys with a similar Kidney Donor Profile Index.

Conclusions: Overall results indicated that the donor constitution has small or moderate effect on post-transplant clinical outcomes.
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http://dx.doi.org/10.2215/CJN.03810319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895487PMC
December 2019

Assessment of Second-Opinion Strategies for Diagnoses of Cutaneous Melanocytic Lesions.

JAMA Netw Open 2019 10 2;2(10):e1912597. Epub 2019 Oct 2.

Department of Translational Research, Institut Curie, Paris, France.

Importance: Histopathologic criteria have limited diagnostic reliability for a range of cutaneous melanocytic lesions.

Objective: To evaluate the association of second-opinion strategies by general pathologists and dermatopathologists with the overall reliability of diagnosis of difficult melanocytic lesions.

Design, Setting, And Participants: This diagnostic study used samples from the Melanoma Pathology Study, which comprises 240 melanocytic lesion samples selected from a dermatopathology laboratory in Bellevue, Washington, and represents the full spectrum of lesions from common nevi to invasive melanoma. Five sets of 48 samples were evaluated independently by 187 US pathologists from July 15, 2013, through May 23, 2016. Data analysis was performed from April 2016 through November 2017.

Main Outcomes And Measures: Accuracy of diagnosis, defined as concordance with an expert consensus diagnosis of 3 experienced pathologists, was assessed after applying 10 different second-opinion strategies.

Results: Among the 187 US pathologists examining the 24 lesion samples, 113 were general pathologists (65 men [57.5%]; mean age at survey, 53.7 years [range, 33.0-79.0 years]) and 74 were dermatopathologists (49 men [66.2%]; mean age at survey, 46.4 years [range, 33.0-77.0 years]). Among the 8976 initial case interpretations, physicians desired second opinions for 3899 (43.4%), most often for interpretation of severely dysplastic nevi. The overall misclassification rate was highest when interpretations did not include second opinions and initial reviewers were all general pathologists lacking subspecialty training (52.8%; 95% CI, 51.3%-54.3%). When considering different second opinion strategies, the misclassification of melanocytic lesions was lowest when the first, second, and third consulting reviewers were subspecialty-trained dermatopathologists and when all lesions were subject to second opinions (36.7%; 95% CI, 33.1%-40.7%). When the second opinion strategies were compared with single interpretations without second opinions, the reductions in misclassification rates for some of the strategies were statistically significant, but none of the strategies eliminated diagnostic misclassification. Melanocytic lesions in the middle of the diagnostic spectrum had the highest misclassification rates (eg, moderately or severely dysplastic nevus, Spitz nevus, melanoma in situ, and pathologic stage [p]T1a invasive melanoma). Variability of in situ and thin invasive melanoma was relatively intractable to all examined strategies.

Conclusions And Relevance: The results of this study suggest that second opinions rendered by dermatopathologists improve reliability of melanocytic lesion diagnosis. However, discordance among pathologists remained high.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.12597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804025PMC
October 2019

Variants Associated with the Ankle Brachial Index Differ by Hispanic/Latino Ethnic Group: a genome-wide association study in the Hispanic Community Health Study/Study of Latinos.

Sci Rep 2019 08 6;9(1):11410. Epub 2019 Aug 6.

Applied Sciences, Premier, Inc, Charlotte, NC, USA.

Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10) for PAD in MESA Hispanics. Among three suggestive associations (p < 10) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.
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http://dx.doi.org/10.1038/s41598-019-47928-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684818PMC
August 2019

GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations.

PLoS One 2019 28;14(6):e0217796. Epub 2019 Jun 28.

Cardiovascular Health Research Unit, University of Washington, Seattle, WA, United States of America.

Background: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.

Methods: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.

Results: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.

Conclusions: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217796PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599128PMC
February 2020

Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.

J Hepatol 2019 09 28;71(3):523-533. Epub 2019 May 28.

Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, WA, United States.

Background & Aims: Hepatocellular carcinoma (HCC) risk varies dramatically in patients with cirrhosis according to well-described, readily available predictors. We aimed to develop simple models estimating HCC risk in patients with alcohol-related liver disease (ALD)-cirrhosis or non-alcoholic fatty liver disease (NAFLD)-cirrhosis and calculate the net benefit that would be derived by implementing HCC surveillance strategies based on HCC risk as predicted by our models.

Methods: We identified 7,068 patients with NAFLD-cirrhosis and 16,175 with ALD-cirrhosis who received care in the Veterans Affairs (VA) healthcare system in 2012. We retrospectively followed them for the development of incident HCC until January 2018. We used Cox proportional hazards regression to develop and internally validate models predicting HCC risk using baseline characteristics at entry into the cohort in 2012. We plotted decision curves of net benefit against HCC screening thresholds.

Results: We identified 1,278 incident cases of HCC during a mean follow-up period of 3.7 years. Mean annualized HCC incidence was 1.56% in NAFLD-cirrhosis and 1.44% in ALD-cirrhosis. The final models estimating HCC were developed separately for NAFLD-cirrhosis and ALD-cirrhosis and included 7 predictors: age, gender, diabetes, body mass index, platelet count, serum albumin and aspartate aminotransferase to √alanine aminotransferase ratio. The models exhibited very good measures of discrimination and calibration and an area under the receiver operating characteristic curve of 0.75 for NAFLD-cirrhosis and 0.76 for ALD-cirrhosis. Decision curves showed higher standardized net benefit of risk-based screening using our prediction models compared to the screen-all approach.

Conclusions: We developed simple models estimating HCC risk in patients with NAFLD-cirrhosis or ALD-cirrhosis, which are available as web-based tools (www.hccrisk.com). Risk stratification can be used to inform risk-based HCC surveillance strategies in individual patients or healthcare systems or to identify high-risk patients for clinical trials.

Lay Summary: Patients with cirrhosis of the liver are at risk of getting hepatocellular carcinoma (HCC or liver cancer) and therefore it is recommended that they undergo surveillance for HCC. However, the risk of HCC varies dramatically in patients with cirrhosis, which has implications on if and how patients get surveillance, how providers counsel patients about the need for surveillance, and how healthcare systems approach and prioritize surveillance. We used readily available predictors to develop models estimating HCC risk in patients with cirrhosis, which are available as web-based tools at www.hccrisk.com.
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http://dx.doi.org/10.1016/j.jhep.2019.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702126PMC
September 2019

The Importance of Uncertainty and Opt-In v. Opt-Out: Best Practices for Decision Curve Analysis.

Med Decis Making 2019 07 20;39(5):491-492. Epub 2019 May 20.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

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http://dx.doi.org/10.1177/0272989X19849436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786944PMC
July 2019

Using ordinal outcomes to construct and select biomarker combinations for single-level prediction.

Diagn Progn Res 2018 21;2. Epub 2018 May 21.

4Department of Biostatistics, University of Washington, Seattle, WA USA.

Background: Biomarker studies may involve an ordinal outcome, such as no, mild, or severe disease. There is often interest in predicting one particular level of the outcome due to its clinical significance.

Methods: A simple approach to constructing biomarker combinations in this context involves dichotomizing the outcome and using a binary logistic regression model. We assessed whether more sophisticated methods offer advantages over this simple approach. It is often necessary to select among several candidate biomarker combinations. One strategy involves selecting a combination based on its ability to predict the outcome level of interest. We propose an algorithm that leverages the ordinal outcome to inform combination selection. We apply this algorithm to data from a study of acute kidney injury after cardiac surgery, where kidney injury may be absent, mild, or severe.

Results: Using more sophisticated modeling approaches to construct combinations provided gains over the simple binary logistic regression approach in specific settings. In the examples considered, the proposed algorithm for combination selection tended to reduce the impact of bias due to selection and to provide combinations with improved performance.

Conclusions: Methods that utilize the ordinal nature of the outcome in the construction and/or selection of biomarker combinations have the potential to yield better combinations.
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http://dx.doi.org/10.1186/s41512-018-0028-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460803PMC
May 2018

Impact of Pre-Analytical Differences on Biomarkers in the ADNI and PPMI Studies: Implications in the Era of Classifying Disease Based on Biomarkers.

J Alzheimers Dis 2019 ;69(1):263-276

Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.

Background: Neurodegenerative diseases require characterization based on underlying biology using biochemical biomarkers. Mixed pathology complicates discovery of biomarkers and characterization of cohorts, but inclusion of greater numbers of patients with different, related diseases with frequently co-occurring pathology could allow better accuracy. Combining cohorts collected from different studies would be a more efficient use of resources than recruiting subjects from each population of interest for each study.

Objective: To explore the possibility of combining existing datasets by controlling pre-analytic variables in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Parkinson's Progression Markers Initiative (PPMI) studies.

Methods: Cerebrospinal fluid (CSF) was collected and processed from 30 subjects according to both the ADNI and PPMI protocols. Relationships between reported levels of Alzheimer's disease (AD) and Parkinson's disease (PD) biomarkers in the same subject under each protocol were examined.

Results: Protocol-related differences were observed for Aβ, but not t-tau or α-syn, and trended different for p-tau and pS129. Values of α-syn differed by platform. Conversion of α-syn values between ADNI and PPMI platforms did not completely eliminate differences in distribution.

Discussion: Factors not captured in the pre-analytical sample handling influence reported biomarker values. Assay standardization and better harmonized characterization of cohorts should be included in future studies of CSF biomarkers.
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http://dx.doi.org/10.3233/JAD-190069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513710PMC
September 2020

Assessing the Clinical Impact of Risk Models for Opting Out of Treatment.

Med Decis Making 2019 02 16;39(2):86-90. Epub 2019 Jan 16.

Fred Hutchinson Cancer Research Center Seattle, WA.

Decision curves are a tool for evaluating the population impact of using a risk model for deciding whether to undergo some intervention, which might be a treatment to help prevent an unwanted clinical event or invasive diagnostic testing such as biopsy. The common formulation of decision curves is based on an opt-in framework. That is, a risk model is evaluated based on the population impact of using the model to opt high-risk patients into treatment in a setting where the standard of care is not to treat. Opt-in decision curves display the population net benefit of the risk model in comparison to the reference policy of treating no patients. In some contexts, however, the standard of care in the absence of a risk model is to treat everyone, and the potential use of the risk model would be to opt low-risk patients out of treatment. Although opt-out settings were discussed in the original decision curve paper, opt-out decision curves are underused. We review the formulation of opt-out decision curves and discuss their advantages for interpretation and inference when treat-all is the standard.
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http://dx.doi.org/10.1177/0272989X18819479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374190PMC
February 2019

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.

Pain 2019 Mar;160(3):579-591

Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.
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http://dx.doi.org/10.1097/j.pain.0000000000001438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377338PMC
March 2019

Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C.

J Hepatol 2018 Nov 21;69(5):1088-1098. Epub 2018 Aug 21.

Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, WA, United States.

Background & Aims: Most patients with hepatitis C virus (HCV) infection will undergo antiviral treatment with direct-acting antivirals (DAAs) and achieve sustained virologic response (SVR). We aimed to develop models estimating hepatocellular carcinoma (HCC) risk after antiviral treatment.

Methods: We identified 45,810 patients who initiated antiviral treatment in the Veterans Affairs (VA) national healthcare system from 1/1/2009 to 12/31/2015, including 29,309 (64%) DAA-only regimens and 16,501 (36%) interferon ± DAA regimens. We retrospectively followed patients until 6/15/2017 to identify incident cases of HCC. We used Cox proportional hazards regression to develop and internally validate models predicting HCC risk using baseline characteristics at the time of antiviral treatment.

Results: We identified 1,412 incident cases of HCC diagnosed at least 180 days after initiation of antiviral treatment during a mean follow-up of 2.5 years (range 1.0-7.5 years). Models predicting HCC risk after antiviral treatment were developed and validated separately for four subgroups of patients: cirrhosis/SVR, cirrhosis/no SVR, no cirrhosis/SVR, no cirrhosis/no SVR. Four predictors (age, platelet count, serum aspartate aminotransferase/√alanine aminotransferase ratio and albumin) accounted for most of the models' predictive value, with smaller contributions from sex, race-ethnicity, HCV genotype, body mass index, hemoglobin and serum alpha-fetoprotein. Fitted models were well-calibrated with very good measures of discrimination. Decision curves demonstrated higher net benefit of using model-based HCC risk estimates to determine whether to recommend screening or not compared to the screen-all or screen-none strategies.

Conclusions: We developed and internally validated models that estimate HCC risk following antiviral treatment. These models are available as web-based tools that can be used to inform risk-based HCC surveillance strategies in individual patients.

Lay Summary: Most patients with hepatitis C virus have been treated or will be treated with direct-acting antivirals. It is important that we can model the risk of hepatocellular carcinoma in these patients, so that we develop the optimum screening strategy that avoids unnecessary screening, while adequately screening those at increased risk. Herein, we have developed and validated models that are available as web-based tools that can be used to guide screening strategies.
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http://dx.doi.org/10.1016/j.jhep.2018.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201746PMC
November 2018

PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.

Nat Commun 2018 07 25;9(1):2904. Epub 2018 Jul 25.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, MD, USA.

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
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http://dx.doi.org/10.1038/s41467-018-04766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060178PMC
July 2018
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