A comparison of the effect of patient-specific versus weight-based protocols to treat vaso-occlusive episodes in the emergency department.

BACKGROUND: Vaso-occlusive crises (VOCs) cause debilitating pain and are a common cause of emergency department (ED) visits, for people with sickle cell disease (SCD). Strategies for achieving optimal pain control vary widely despite evidence-based guidelines. We tested existing guidelines and hypothesized that a patient-specific pain protocol (PSP) written by their SCD provider may be more effective than weight-based (WB) dosing of parenteral opiate medication, in relieving pain. METHODS: This study was a prospective, randomized controlled trial comparing a PSP versus WB protocol for patients presenting with VOCs to six EDs. Patients were randomized to a PSP or WB protocol prior to an ED visit. The SCD provider wrote their protocol and placed it in the electronic health record for future ED visits with VOC exclusion criteria that included preexisting PSP excluding parenteral opioid analgesia or outpatient use of buprenorphine or methadone or highly suspected for COVID-19. Pain intensity scores, side effects, and safety were obtained every 30 min for up to 6 h post-ED bed placement. The primary outcome was change in pain intensity score from placement in an ED space to disposition or 6 h. RESULTS: A total of 328 subjects were randomized; 104 participants enrolled (ED visit, target n = 230) with complete data for 96 visits. The study was unable to reach the target sample size and stopped early due to the impact of COVID-19. We found no significant differences between groups in the primary outcome; patients randomized to a PSP had a shorter ED length of stay (p = 0.008), and the prevalence of side effects was low in both groups. Subjects in both groups experienced both a clinically meaningful and a statistically significant decrease in pain (27 mm on a 0- to 100-mm scale). CONCLUSIONS: We found a shorter ED length of stay for patients assigned to a PSP. Patients in both groups experienced good pain relief without significant side effects.

Multiparametric Data-driven Imaging Markers: Guidelines for Development, Application and Reporting of Model Outputs in Radiomics.

This paper is the fifth in a five-part series on statistical methodology for performance assessment of multi-parametric quantitative imaging biomarkers (mpQIBs) for radiomic analysis. Radiomics is the process of extracting visually imperceptible features from radiographic medical images using data-driven algorithms. We refer to the radiomic features as data-driven imaging markers (DIMs), which are quantitative measures discovered under a data-driven framework from images beyond visual recognition but evident as patterns of disease processes irrespective of whether or not ground truth exists for the true value of the DIM. This paper aims to set guidelines on how to build machine learning models using DIMs in radiomics and to apply and report them appropriately. We provide a list of recommendations, named RANDAM (an abbreviation of "Radiomic ANalysis and DAta Modeling"), for analysis, modeling, and reporting in a radiomic study to make machine learning analyses in radiomics more reproducible. RANDAM contains five main components to use in reporting radiomics studies: design, data preparation, data analysis and modeling, reporting, and material availability. Real case studies in lung cancer research are presented along with simulation studies to compare different feature selection methods and several validation strategies.

Multiparametric Quantitative Imaging in Risk Prediction: Recommendations for Data Acquisition, Technical Performance Assessment, and Model Development and Validation.

Combinations of multiple quantitative imaging biomarkers (QIBs) are often able to predict the likelihood of an event of interest such as death or disease recurrence more effectively than single imaging measurements can alone. The development of such multiparametric quantitative imaging and evaluation of its fitness of use differs from the analogous processes for individual QIBs in several key aspects. A computational procedure to combine the QIB values into a model output must be specified. The output must also be reproducible and be shown to have reasonably strong ability to predict the risk of an event of interest. Attention must be paid to statistical issues not often encountered in the single QIB scenario, including overfitting and bias in the estimates of model performance. This is the fourth in a five-part series on statistical methodology for assessing the technical performance of multiparametric quantitative imaging. Considerations for data acquisition are discussed and recommendations from the literature on methodology to construct and evaluate QIB-based models for risk prediction are summarized. The findings in the literature upon which these recommendations are based are demonstrated through simulation studies. The concepts in this manuscript are applied to a real-life example involving prediction of major adverse cardiac events using automated plaque analysis.

Multiparametric Quantitative Imaging Biomarker as a Multivariate Descriptor of Health: A Roadmap.

Multiparametric quantitative imaging biomarkers (QIBs) offer distinct advantages over single, univariate descriptors because they provide a more complete measure of complex, multidimensional biological systems. In disease, where structural and functional disturbances occur across a multitude of subsystems, multivariate QIBs are needed to measure the extent of system malfunction. This paper, the first Use Case in a series of articles on multiparameter imaging biomarkers, considers multiple QIBs as a multidimensional vector to represent all relevant disease constructs more completely. The approach proposed offers several advantages over QIBs as multiple endpoints and avoids combining them into a single composite that obscures the medical meaning of the individual measurements. We focus on establishing statistically rigorous methods to create a single, simultaneous measure from multiple QIBs that preserves the sensitivity of each univariate QIB while incorporating the correlation among QIBs. Details are provided for metrological methods to quantify the technical performance. Methods to reduce the set of QIBs, test the superiority of the mp-QIB model to any univariate QIB model, and design study strategies for generating precision and validity claims are also provided. QIBs of Alzheimer's Disease from the ADNI merge data set are used as a case study to illustrate the methods described.

Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate.

BACKGROUND & AIMS: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS). METHODS: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases. RESULTS: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10-7), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10-7) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10-5) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model. CONCLUSIONS: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.

Multiparametric Quantitative Imaging Biomarkers for Phenotype Classification: A Framework for Development and Validation.

This manuscript is the third in a five-part series related to statistical assessment methodology for technical performance of multi-parametric quantitative imaging biomarkers (mp-QIBs). We outline approaches and statistical methodologies for developing and evaluating a phenotype classification model from a set of multiparametric QIBs. We then describe validation studies of the classifier for precision, diagnostic accuracy, and interchangeability with a comparator classifier. We follow with an end-to-end real-world example of development and validation of a classifier for atherosclerotic plaque phenotypes. We consider diagnostic accuracy and interchangeability to be clinically meaningful claims for a phenotype classification model informed by mp-QIB inputs, aiming to provide tools to demonstrate agreement between imaging-derived characteristics and clinically established phenotypes. Understanding that we are working in an evolving field, we close our manuscript with an acknowledgement of existing challenges and a discussion of where additional work is needed. In particular, we discuss the challenges involved with technical performance and analytical validation of mp-QIBs. We intend for this manuscript to further advance the robust and promising science of multiparametric biomarker development.

Value of liver biopsy in the diagnosis of drug-induced liver injury.

BACKGROUND & AIMS: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. METHODS: Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. RESULTS: Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. CONCLUSIONS: Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. LAY SUMMARY: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.

Differences in NT-proBNP Response and Prognosis in Men and Women With Heart Failure With Reduced Ejection Fraction.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT-proBNP response and whether the therapeutic goal of NT-proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT-proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all-cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT-proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE-IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline-directed medical therapy was less intense over time in women. The absolute NT-proBNP values were consistently lower in women; however, the change in NT-proBNP and clinical outcomes were similar. After adjustment, women achieving the NT-proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT-proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT-proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline-directed medical therapy in women, which may result in greater NT-proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840.

Trial design of comparing patient-specific versus weight-based protocols to treat vaso-occlusive episodes in sickle cell disease (COMPARE-VOE).

OBJECTIVES: Painful vaso-occlusive episodes (VOE) are the most common reason for emergency department (ED) visits experienced by patients with sickle cell disease (SCD). The National Heart, Lung and Blood Institute (NHLBI) evidence-based recommendations for VOE treatment are based primarily on expert opinion. In this randomized controlled trial (RCT), we will compare changes in pain scores between patients randomized to a patient-specific analgesic protocol versus those randomized to a weight-based analgesic protocol, as recommended by the NHLBI guidelines. METHODS: We report the rationale and design of a multi-site, phase III, single-blinded, RCT to be conducted in six EDs in the United States. Eligible participants will be randomized after providing consent, anticipating 50% of those randomized would have an ED visit during the enrollment period. A total of 230 participants with one VOE ED visit provides sufficient power to detect a clinically significant difference in pain score reductions of 14 between groups with 0.05 type I error. Uniquely, this trial randomizes participants in a larger population than the study population, given the impossibility of consenting and randomizing participants during emergencies. The primary endpoint is the change in pain scores in the ED from time of placement in treatment area to time of disposition (hospitalization, discharged home, or assigned to observation status) or a maximum treatment duration of 6 hours. Additional outcomes include hospitalizations and ED visits seven days post enrollment, side effects, and safety assessments. CONCLUSIONS: The COMPARE-VOE study design will provide high-level evidence to support the NHLBI VOE treatment guidelines.

Severe and protracted cholestasis in 44 young men taking bodybuilding supplements: assessment of genetic, clinical and chemical risk factors.

BACKGROUND: Bodybuilding supplements can cause a profound cholestatic syndrome. AIM: To describe the drug-Induced liver injury network's experience with liver injury due to bodybuilding supplements. METHODS: Liver injury pattern, severity and outcomes, potential genetic associations, and exposure to anabolic steroids by product analysis were analysed in prospectively enrolled subjects with bodybuilding supplement-induced liver injury with causality scores of probable or higher. RESULTS: Forty-four males (mean age 33 years) developed liver injury with a median latency of 73 days. Forty-one per cent presented with hepatocellular pattern of liver injury as defined by the R > 5 ([Fold elevation of ALT] ÷ [Fold elevation of Alk Phos] (mean, range = 6.4, 0.5-31.4, n = 42) despite all presenting with clinical features of cholestatic liver injury (100% with jaundice and 84% with pruritus). Liver biopsy (59% of subjects) demonstrated a mild hepatitis and profound cholestasis in most without bile duct injury, loss or fibrosis. Seventy-one per cent were hospitalised, and none died or required liver transplantation. In some, chemical analysis revealed anabolic steroid controlled substances not listed on the label. No enrichment of genetic variants associated with cholestatic syndromes was found, although mutations in ABCB11 (present in up to 20%) were significantly different than in ethnically matched controls. CONCLUSIONS: Patients with bodybuilding supplements liver injury uniformly presented with cholestatic injury, which slowly resolved. The ingested products often contained anabolic steroids not identified on the label, and no enrichment in genetic variants was found, indicating a need for additional studies.

Tools for causality assessment in drug-induced liver disease.

PURPOSE OF REVIEW: There are three liver-specific causality assessment tools currently available to guide clinical diagnosis of Drug-Induced Liver Injury (DILI): Roussel-Uclaf Causality Assessment Method (RUCAM), Digestive-Disease-Week Japan 2004 scale (DDW-J), and Clinical Diagnostic Scale (CDS). The purpose of this review is to assess these tools and discuss how to improve the causality assessment process as a whole. RECENT FINDINGS: Existing DILI-specific causality assessment tools are surprisingly similar and exhibit only minor differences in point allocation. But difference in threshold for likelihood of being DILI. We reviewed the literature on currently used causality assessment tools, identified areas for future improvement, and herein propose approaches for refinement. Opportunities to improve current models, as well as the assessment process, in general, include in particular provision of more precise clinical detail and to perhaps add new components to scoring systems. For example, the incorporation of drug-specific clinical signature patterns, accounting for a drug's inherent hepatotoxicity potential, and/or incorporation of other drug properties to scoring systems may allow enhancement. Further, more systemic exclusion of competing diagnoses is needed. Finally, causality assessment processes will likely benefit from a data-driven and computer-assisted approach. SUMMARY: Current tools used for DILI adjudication are imperfect. Avenues to improve these tools are described.

Incident anaemia in older adults with heart failure: rate, aetiology, and association with outcomes.

AIMS: Limited data exist on the epidemiology, evaluation, and prognosis of otherwise unexplained anaemia of the elderly in heart failure (HF). Thus, we aimed to determine the incidence of anaemia, to characterize diagnostic testing patterns for potentially reversible causes of anaemia, and to evaluate the independent association between incident anaemia and long-term morbidity and mortality. METHODS AND RESULTS: Within the Cardiovascular Research Network (CVRN), we identified adults age ≥65 years with diagnosed HF between 2005 and 2012 and no anaemia at entry. Incident anaemia was defined using World Health Organization (WHO) haemoglobin thresholds (<13.0 g/dL in men; <12.0 g/dL in women). All-cause death and hospitalizations for HF and any cause were identified from electronic health records. Among 38 826 older HF patients, 22 163 (57.1%) developed incident anaemia over a median (interquartile range) follow-up of 2.9 (1.2-5.6) years. The crude rate [95% confidence interval (CI)] per 100 person-years of incident anaemia was 26.4 (95% CI 26.0-26.7) and was higher for preserved ejection fraction (EF) [29.2 (95% CI 28.6-29.8)] compared with borderline EF [26.5 (95% CI 25.4-27.7)] or reduced EF [26.6 (95% CI 25.8-27.4)]. Iron indices, vitamin B12 level, and thyroid testing were performed in 20.9%, 14.9%, and 40.2% of patients, respectively. Reduced iron stores, vitamin B12 deficiency, and/or hypothyroidism were present in 29.7%, 3.2%, and 18.6% of tested patients, respectively. In multivariable analyses, incident anaemia was associated with excess mortality [hazard ratio (HR) 2.14, 95% CI 2.07-2.22] as well as hospitalization for HF (HR 1.80, 95% CI 1.72-1.88) and any cause (HR 1.77, 95% CI 1.72-1.83). CONCLUSION: Among older adults with HF, incident anaemia is common and independently associated with substantially increased risks of morbidity and mortality. Additional research is necessary to clarify the value of routine evaluation and treatment of potentially reversible causes of anaemia.

Correction: Cytokine profiles in acute liver injury-Results from the US Drug-Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group.

[This corrects the article DOI: 10.1371/journal.pone.0206389.].

NT-proBNP Goal Achievement Is Associated With Significant Reverse Remodeling and Improved Clinical Outcomes in HFrEF.

OBJECTIVES: This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling. BACKGROUND: In patients with heart failure with reduced ejection fraction (HFrEF), it is unclear if lowering natriuretic peptides reflects structural and functional changes in the heart. This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling. METHODS: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) Echo Substudy was a multicenter study that randomized 268 patients with HFrEF (EF ≤40%) to either pro-B-type natriuretic peptide (NT-proBNP)-guided treatment or usual care. Echocardiograms were performed at baseline and 12 months in 124 patients. Remodeling indices and clinical outcomes were compared between treatment arms and by achievement of the NT-proBNP goal of <1,000 pg/ml at 12 months. RESULTS: At 12 months, the changes in EF and LV volumes were similar between the biomarker-guided and usual care arms with no difference in clinical outcomes; however, lowering NT-proBNP to <1,000 pg/ml, regardless of treatment strategy, was associated with a significantly greater increase in EF compared with those not reaching goal (9.9 ± 8.8% vs. 2.9 ± 7.9%; p < 0.001) and lower LV volumes. The extent of reverse remodeling correlated with the change in NT-proBNP: a decrease of 1,000 pg/ml was associated with an increase in EF of 6.7% and a reduction in systolic and diastolic volumes of 17.3 ml/m2 and 15.7 ml/m2, respectively. Adverse events were significantly lower among patients achieving the NT-proBNP goal (p < 0.001). CONCLUSIONS: Among patients with HFrEF, lowering NT-proBNP to <1,000 pg/ml by 12 months was associated with significant reverse remodeling and improved outcomes. A greater reduction in NT-proBNP was associated with more extensive reverse remodeling. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

Cytokine profiles in acute liver injury-Results from the US Drug-Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group.

Changes in levels of cytokines and chemokines have been proposed as possible biomarkers of tissue injury, including liver injury due to drugs. Recently, in acute drug-induced liver injury (DILI), we showed that 19 of 27 immune analytes were differentially expressed and that disparate patterns of immune responses were evident. Lower values of serum albumin (< 2.8 g/dL) and lower levels of only four analytes, namely, IL-9, IL-17, PDGF-bb, and RANTES, were highly predictive of early death [accuracy = 96%]. The goals of this study were to assess levels of the same 27 immune analytes in larger numbers of subjects to learn whether the earlier findings would be confirmed in new and larger cohorts of subjects, compared with a new cohort of healthy controls. We studied 127 subjects with acute DILI enrolled into the US DILIN. We also studied 118 subjects with severe acute liver injury of diverse etiologies, enrolled into the ALF SG registry of subjects. Controls comprised 63 de-identified subjects with no history of liver disease and normal liver tests. Analytes associated with poor outcomes [death before 6 months, n = 32 of the total of 232 non-acetaminophen (Apap) subjects], were lower serum albumin [2.6 vs 3.0 g/dL] and RANTES [6,458 vs 8,999 pg/mL] but higher levels of IL-6 [41 vs 18], IL-8 [78 vs 48], and MELD scores [30 vs 24]. Similar patterns were observed for outcome of death/liver transplant within 6 months. A model that included only serum albumin < 2.8 g/dL and RANTES below its median value of 11,349 had 83% (or 81%) accuracy for predicting early death (or early death/liver transplant) in 127 subjects from DILIN. No patterns of serum immune analytes were reflective of the etiologies of acute liver failure, but there were cytokine patterns that predicted prognosis in both acute DILI and ALF.

Simultaneous Risk Factor Control Using Telehealth to slOw Progression of Diabetic Kidney Disease (STOP-DKD) study: Protocol and baseline characteristics of a randomized controlled trial.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the United States. Multiple risk factors contribute to DKD development, yet few interventions target more than a single DKD risk factor at a time. This manuscript describes the study protocol, recruitment, and baseline participant characteristics for the Simultaneous Risk Factor Control Using Telehealth to slOw Progression of Diabetic Kidney Disease (STOP-DKD) study. The STOP-DKD study is a randomized controlled trial designed to evaluate the effectiveness of a multifactorial behavioral and medication management intervention to mitigate kidney function decline at 3 years compared to usual care. The intervention consists of up to 36 monthly educational modules delivered via telephone by a study pharmacist, home blood pressure monitoring, and medication management recommendations delivered electronically to primary care physicians. Patients seen at seven primary care clinics in North Carolina, with diabetes and [1] uncontrolled hypertension and [2] evidence of kidney dysfunction (albuminuria or reduced estimated glomerular filtration rate [eGFR]) were eligible to participate. Study recruitment completed in December 2014. Of the 281 participants randomized, mean age at baseline was 61.9; 52% were male, 56% were Black, and most were high school graduates (89%). Baseline co-morbidity was high- mean blood pressure was 134/76 mmHg, mean body mass index was 35.7 kg/m2, mean eGFR was 80.7 ml/min/1.73 m2, and mean glycated hemoglobin was 8.0%. Experiences of recruiting and implementing a comprehensive DKD program to individuals at high risk seen in the primary care setting are provided. TRIAL REGISTRATION: NCT01829256.

Echocardiography Core Laboratory Reproducibility of Cardiac Safety Assessments in Cardio-Oncology.

BACKGROUND: As the potential for cancer therapy-related cardiac dysfunction is increasingly recognized, there is a need for the standardization of echocardiographic measurements and cut points to guide treatment. The aim of this study was to determine the reproducibility of cardiac safety assessments across two academic echocardiography core laboratories (ECLs) at the University of Pennsylvania and the Duke Clinical Research Institute. METHODS: To harmonize the application of guideline-recommended measurement conventions, the ECLs conducted multiple training sessions to align measurement practices for traditional and emerging assessments of left ventricular (LV) function. Subsequently, 25 echocardiograms taken from patients with breast cancer treated with doxorubicin with or without trastuzumab were independently analyzed by each laboratory. Agreement was determined by the proportion (coverage probability [CP]) of all pairwise comparisons between readers that were within a prespecified minimum acceptable difference. Persistent differences in measurement techniques between laboratories triggered retraining and reassessment of reproducibility. RESULTS: There was robust reproducibility within each ECL but differences between ECLs on calculated LV ejection fraction and mitral inflow velocities (all CPs < 0.80); four-chamber global longitudinal strain bordered acceptable reproducibility (CP = 0.805). Calculated LV ejection fraction and four-chamber global longitudinal strain were sensitive to small but systematic interlaboratory differences in endocardial border definition that influenced measured LV volumes and the speckle-tracking region of interest, respectively. On repeat analyses, reproducibility for mitral velocities (CP = 0.940-0.990) was improved after incorporating multiple-beat measurements and homogeneous image selection. Reproducibility for four-chamber global longitudinal strain was unchanged after efforts to develop consensus between ECLs on endocardial border determinations were limited primarily by a lack of established reference standards. CONCLUSIONS: High-quality quantitative echocardiographic research is feasible but requires a commitment to reproducibility, adherence to guideline recommendations, and the time, care, and attention to detail to establish agreement on measurement conventions. These findings have important implications for research design and clinical care.

Novel Approaches to Causality Adjudication in Drug-Induced Liver Disease.

PURPOSE OF REVIEW: Drug induced liver injury (DILI) is a complex diagnosis dominantly based of exclusion. RECENT FINDINGS: Currently available causality assessment instruments are considered to be suboptimal. Expert opinion appears to be best method to adjudicate causality, but is impractical to implement on a wide scale basis. Thus, new approaches are needed, for example improving the specificity of current scoring systems. A further option would be to develop a system that utilizes computer-based scoring - which would reduce human error. Additionally, it would be ideal to have available drug specific scoring systems, based on drugs' characteristic "phenotypes" (presentation and pattern of injury). Eventually, a validated system could be integrated within the electronic health information system. SUMMARY: This review highlights an avenue to an improved Causality Assessment Tool.

Death and liver transplantation within 2 years of onset of drug-induced liver injury.

Drug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities is poorly characterized, particularly when fatalities occur >26 weeks after DILI onset. We analyzed patients in the US Drug-Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by eight network investigators and categorized as DILI having a primary, a contributory, or no role in the fatality. We subcategorized primary role cases as acute, chronic, acute-on-chronic, or acute cholestatic liver failure. For contributory and no role cases, we assigned a primary cause of death. Among 1,089 patients, 107 (9.8%) fatalities occurred within 2 years. DILI had a primary role in 68 (64%), a contributory role in 15 (14%), and no role in 22 (21%); 2 had insufficient data. Among primary role cases, 74% had acute, 13% chronic, 7% acute on chronic, and 6% acute cholestatic failure. For the 15 contributory role cases, common causes of death included sepsis, malignancy, and severe cutaneous reactions with multiorgan failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis, and thrombocytopenia were independently associated with DILI fatalities. New R ratio Hy's law had a higher positive predictive value for overall fatality (14% versus 10%) and a stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy's law (hazard ratio, 6.2, 95% confidence interval 3.4-11.1, versus 2.2, 95% confidence interval 1.3-3.7). CONCLUSIONS: DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these had nonacute liver failure courses. New R ratio Hy's law better identifies risk for death compared to the original Hy's law. (Hepatology 2017;66:1275-1285).

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.