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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).Transcriptome-wide association (TWAS) and genome-wide association (GWAS) 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 to 1358 and 403 non-AC-DILI cases.TWAS revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7x10We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B*15:18. GRS based on the five risk variants may assist AC-DILI causality assessment and risk management.

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.

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.

BACKGROUND: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G. cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G. cambogia either alone (n=5) or in combination with green tea (n=16) or Ashwagandha (n=1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G. cambogia and 103 patients from other HDS. RESULTS: Patients who took G. cambogia were between 17 to 54 years, with liver injury arising 13 to 223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G. cambogia group (p

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.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.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.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.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.

A kappa-like classification statistic is proposed for assessing the fit of GEE regression models with a categorical response. The proposed statistic is a summary measure depicting how well categorical responses are predicted from the fitted GEE model. The statistic takes on a value of 1 if prediction is perfect and a value of 0 if the fitted model fares no better than random chance, i.e., fitting the repeated categorical responses with an intercept-only model. To demonstrate the usefulness of the classification statistic, we present simulation results as well as two examples from biomedical studies.

HIV (Human Immunodeficiency Virus) researchers are often concerned with the correlation between HIV viral load measurements and CD4 + lymphocyte counts. Due to the lower limits of detection (LOD) of the available assays, HIV viral load measurements are subject to left-censoring. Motivated by these considerations, the maximum likelihood (ML) method under normality assumptions was recently proposed for estimating the correlation between two continuous variables that are subject to left-censoring. In this paper, we propose a generalized estimating equations (GEE) approach as an alternative to estimate such a correlation coefficient. We investigate the robustness to the normality assumption of the ML and the GEE approaches via simulations. An actual HIV data example is used for illustration.

In many clinical trials, information is collected on both the fre- quency of event occurrence and the severity of each event. For example, in evaluating a new anti-epileptic medication both the total number of seizures a patient has during the study period as well as the severity (e.g., mild, severe) of each seizure could be measured. In order to arrive at a full picture of drug or treatment performance, one needs to jointly model the number of events and their correlated ordinal severity measures. A separate analysis is not recommended as it is inefficient and can lead to what we define as "zero length bias" in estimates of treatment effect on severity. This paper proposes a general, likelihood based, marginal regression model for jointly modeling the number of events and their correlated ordinal severity measures. We de- scribe parameter estimation issues and derive the Fisher information matrix for the joint model in order to obtain the asymptotic covariance matrix of the parameter estimates. A limited simulation study is conducted to exam- ine the asymptotic properties of the maximum likelihood estimators. Using this joint model, we propose tests that incorporate information from both the number of events and their correlated ordinal severity measures. The methodology is illustrated with two examples from clinical trials: the first concerning a new drug treatment for epilepsy; the second evaluating the effect of a cholesterol lowering medication on coronary artery disease.

Existing indices of observer agreement for continuous data, such as the intraclass correlation coefficient or the concordance correlation coefficient, measure the total observer-related variability, which includes the variabilities between and within observers. This work introduces a new index that measures the interobserver variability, which is defined in terms of the distances among the 'true values' assigned by different observers on the same subject. The new coefficient of interobserver variability (CIV) is defined as the ratio of the interobserver and the total observer variability. We show how to estimate the CIV and how to use bootstrap and ANOVAbased methods for inference. We also develop a coefficient of excess observer variability, which compares the total observer variability to the expected total observer variability when there are no differences among the observers. This coefficient is a simple function of the CIV. In addition, we show how the value of the CIV, estimated from an agreement study, can be used in the design of measurements studies. We illustrate the new concepts and methods by two examples, where (1) two radiologists used calcium scores to evaluate the severity of coronary artery arteriosclerosis, and (2) two methods were used to measure knee joint angle.

BACKGROUND AND AIMS Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

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.

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.

Objectives The aim of this study was to provide an overview of the presenting features, etiologies, and outcomes of children enrolled in the Drug-induced Liver Injury Network (DILIN) prospective and retrospective studies. Methods Consecutive definite, highly likely, or probable cases in children enrolled into the ongoing DILIN prospective and retrospective studies between September 2004 and February 2017 were reviewed. Results Fifty-seven cases were adjudicated as definite (14), highly likely (30), or probable (13) DILI. Median age was 14.3 years (1.7-17.9), 67% female, and 82% Caucasian. At DILI onset, 82% had hepatocellular injury with a median alanine aminotransferase of 411 U/L (33-4185), alkaline phosphatase 203 U/L (62-1177), and total bilirubin 3.3 mg/dL (0.2-33.9). The median duration of suspect medication use was 55 days (1-2789) and the most frequently implicated individual agents were minocycline (n = 11) and valproate (n = 6). Sixty-three percent were hospitalized and 3 (5%) underwent liver transplant within 1 month of DILI onset. Among 46 children followed for at least 6 months, 8 (17%) met criteria for chronic DILI with 6 of them having persistent liver injury at 24 months of follow-up. A genome-wide association study in 39 Caucasian children focusing on regions associated with pediatric cholestatic liver disease failed to demonstrate any single nucleotide polymorphism associated with DILI susceptibility or outcome. Conclusions Antimicrobials (51%) and antiepileptic drugs (21%) are the most frequently implicated agents in pediatric DILI patients. Although the majority of cases are self-limited, there is potential for serious morbidity including acute liver failure, chronic liver injury, and death.

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.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.Current tools used for DILI adjudication are imperfect. Avenues to improve these tools are described.

This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.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.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.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/mAmong 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).

BACKGROUND/AIMS Allopurinol can cause HLA class I-associated life-threatening severe skin reactions. However, HLA risk and association with clinical features in allopurinol hepatotoxicity are unknown. METHODS Eleven of 17 patients with suspected allopurinol hepatotoxicity enrolled into the Drug-Induced Liver Injury Network were adjudicated as definite, highly likely, or probable. High-resolution HLA sequencing was undertaken in cases and compared with population and other DILI controls. RESULT Median age was 60 years, 54% were male, and 63% African- American, 27% Caucasian, and 9% Hispanic. Patients presented at a median of 52 days after starting allopurinol, all were hospitalized and six were jaundiced. The median peak ALT, alkaline phosphatase, and total bilirubin were 525 U/L, 521 U/L, and 7.8 mg/dl, respectively, with a median R ratio of 2.7 at onset. During follow-up, nine patients were treated with corticosteroids including five of the six with suspected DRESS. Three patients died including two from liver failure at 38 and 45 days after onset, and the remaining eight recovered. Three HLA alleles were found to be overrepresented in allopurinol cases, particularly in African Americans: HLA-B*58:01, which has been previously linked to severe skin reactions, and HLA-B*53:01 and HLA-A*34:02, all of which are more frequently found in African Americans than European Americans or Latinos. CONCLUSIONS Allopurinol hepatotoxicity is associated with systemic hypersensitivity, a short latency to onset, African-American race and three HLA risk alleles, HLA-B*58:01, HLA-B*53:01, and HLA-A*34:02-58:01 testing may help confirm a diagnosis of hepatotoxicity in allopurinol-treated patients.

Background : Kratom is a botanical product used as an opium substitute with abuse potential. Methods : Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort. Results : Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients. Conclusion : Kratom can cause severe liver injury with jaundice.

We evaluated whether low-grade albuminuria or black race modulates ambulatory blood pressure (BP) or nocturnal BP response to the DASH diet. Among 202 adults enrolled in the DASH multicenter trial who were fed the DASH or control diet for 8 weeks, reductions in 24-hour daytime and nighttime SBP and DBP were significantly larger for DASH compared to control. Median changes in nocturnal BP dipping were not significant. Compared to urine albumin excretion of

High-quality imaging data are critical when echocardiography is used for serial assessments of study and safety endpoints for regulatory decision-making. Although core laboratories (ECL) improve analytic consistency [(1–3)][1], site image quality is also required and was suboptimal in up to 50%

Drug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities ispoorly characterized particularly when fatalities occur > 26 weeks after DILI onset. We analyzed patients in the U.S. Drug-Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by 8 Network investigators and categorized as DILI having a primary, 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 1089 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 multi-organ failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis and thrombocytopenia were independently associated with DILI fatalities. nR Hy’s Law had a higher positive predictive value for overall fatality (14% vs. 10%) and stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy’s Law (HR: 6.2, CI 3.4 – 11.1 vs. 2.2, CI 1.3–3.7). DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these have non-acute liver failure courses. nR Hy’s Law better identifies risk for death compared to the original Hy’s Law.

Background and aim Gender and menopause may contribute to type and severity of drug-induced liver injury (DILI) by influencing host responses to injury. The aim of this study was to assess the associations of gender and female age 50 [a proxy of menopause] with histologic features of liver injury in 212 adults enrolled in the Drug-Induced Liver Injury Network (DILIN) registry Methods All participants had a causality score of at least ‘probable’, a liver biopsy within 30 days of DILI onset, and no prior chronic liver disease. Biochemical and histologic injury types were classified as hepatocellular or cholestatic/mixed injury. The cohort was divided into three gender/age categories: men (41.0%), women < 50 years (27.4%), and women ≥ 50 years of age (31.6%). Interaction of gender and age category (≥50 or not) was assessed Results Hepatocellular injury was more prevalent in women < 50 years vs. others (p=0.002). After adjusting for biochemical injury types, black race and possible aging effects, more severe interface hepatitis was noted in biopsies of women < 50 years compared to those of men and women ≥ 50 years (p=0.009 and p=0.055, respectively). Compared to those of men, biopsies of women showed greater plasma cell infiltration, hepatocyte apoptosis, hepatocyte rosettes, and lobular disarray but less iron-positive hepatocytes and histological cholestasis (p

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.

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 ( 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.

Background & Aims Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcomes are not well understood. We investigated the association between comorbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months. Methods A multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the Drug-Induced Liver Injury Network prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson Comorbidity Index—patients with scores higher than 2 were considered to have significant comorbidities. Results Six-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio, 5.4; 95% confidence interval [CI], 2.1–13.8), Model for End-Stage Liver Disease score (odds ratio, 1.11; 95% CI, 1.04–1.17), and serum level of albumin at presentation (odds ratio, 0.39; 95% CI, 0.2–0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months, with c-statistic values of 0.89 (95% CI, 0.86–0.94) in the discovery cohort and 0.91 (95% CI, 0.83–0.99) in the validation cohort. We developed a web-based calculator for use in the clinic to determine risk of death within 6 months for patients with suspected DILI. Conclusions We developed and validated a model based on comorbidity burden, Model for End-Stage Liver Disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.

BACKGROUND & AIMS: The aims were to review the diagnosis, testing and presentation of acute hepatitis C (HCV) in patients initially diagnosed to have drug-induced liver injury (DILI) enrolled in the US DILI Network. METHODS: All patients with suspected DILI underwent testing for competing causes of liver injury and returned for 6-month follow-up. Causality was adjudicated by consensus expert opinion. RESULTS: Between 2004–2016, 1518 patients were enrolled and adjudicated and underwent 6 months of follow up. Initial locally acquired anti-HCV results were available in 1457 (96%), but HCV RNA in only 795 (52%). Stored sera were available for repeat testing, so that results were available on all 1518 patients (1457 for anti-HCV and 1482 for HCV RNA). 104 subjects (6.9%) had evidence of HCV infection- 10 positive for HCV RNA alone, 16 for anti-HCV alone and 78 for both. All 104 HCV-positive cases were reviewed and 23 cases were adjudicated as acute HCV. All presented with acute hepatocellular injury with median ALT 1448 U/L, alkaline phosphatase 232 U/L and total bilirubin 10.8 mg/dL. 22 (96%) patients were jaundiced. While all 23 cases initially had been suspected of having DILI, 19 were adjudicated as acute HCV and not DILI at the 6 month follow-up; while 4 were still considered DILI. CONCLUSIONS: 23 of 1518 (1.5%) cases of suspected DILI were due to acute HCV infection. We recommend that initial and follow up HCV RNA testing should be performed to exclude HCV in patients with acute hepatocellular injury and suspected DILI.

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.

The 36-Item Short Form Health Survey (SF-36) has been widely used to measure quality of life. Reliability has been traditionally assessed by intraclass correlation coefficient (ICC), which is equivalent to Cronbach's alpha theoretically. However, it is a scaled assessment of reliability and does not indicate the extent of differences because of measurement error. In this paper, total deviation index (TDI) is used to interpret the magnitude of measurement error for SF-36, and a new formula for computing TDI for average item score is proposed. The interpretation based on TDI is simple and intuitive by providing, with a high probability, the expected difference that is because of measurement error. We also show that a high value of ICC does not always correspond to a smaller magnitude of measurement error, which indicates that ICC can sometimes provide a false sense of high reliability. The methodology is illustrated with reported SF-36 data from the literature and from real data in the Arthritis Self-Management Program. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical core laboratories, such as Echocardiography core laboratories, are increasingly used in clinical studies with imaging outcomes as primary, secondary, or surrogate endpoints. While many factors contribute to the quality of measurements of imaging variables, an essential step in ensuring the value of imaging data includes formal assessment and control of reproducibility via intra-observer and inter-observer reliability. There are many different agreement/reliability indices in the literature. However, different indices may lead to different conclusions and it is not clear which index is the preferred choice as an overall indication of data quality and a tool for providing guidance on improving quality and reliability in a core lab setting. In this paper, we pre-specify the desirable characteristics of an agreement index for assessing and improving reproducibility in a core lab setting; we compare existing agreement indices in terms of these characteristics to choose a preferred index. We conclude that, among the existing indices reviewed, the coverage probability for assessing agreement is the preferred agreement index on the basis of computational simplicity, its ability for rapid identification of discordant measurements to provide guidance for review and retraining, and its consistent evaluation of data quality across multiple reviewers, populations, and continuous/categorical data.

Background Although the Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure (BP) for adults with normal kidney function, evidence is lacking regarding its safety and efficacy in chronic kidney disease (CKD). We aimed to test the effects of the DASH diet on serum electrolytes and BP in adults with moderate CKD. Methods In a prospective before–after feeding study, 11 adults with an estimated glomerular filtration rate of 30–59 mL/min/1.73 m2 and medication-treated hypertension were provided a reduced-sodium, run-in diet for 1 week followed by a reduced-sodium, DASH diet for 2 weeks. Changes in serum electrolytes and BP were compared pre–post DASH. Results Eleven participants underwent feeding; 1 completed 1 week and 10 completed 2 weeks of DASH. Compared with baseline, DASH modestly increased serum potassium at 1 week (mean ± standard deviation, +0.28 ± 0.4 mg/dL; P = 0.043) but had no significant effect on potassium at 2 weeks (+0.15 ± 0.28 mg/dL; P = 0.13). Serum bicarbonate was reduced (−2.5 ± 3.0 mg/dL; P = 0.03) at 2 weeks. Neither incident hyperkalemia nor new onset metabolic acidosis was observed. Clinic BP and mean 24-h ambulatory BP was unchanged. DASH significantly reduced mean nighttime BP (−5.3 ± 5.8 mmHg; P = 0.018), and enhanced percent declines in both nocturnal systolic BP (−2.1% to −5.1%; P = 0.004) and diastolic BP (−3.7% to −10.0%; P = 0.008). Conclusions These pilot data suggest that a reduced-sodium DASH dietary pattern does not cause acute metabolic events in adults with moderate CKD and may improve nocturnal BP. Definitive studies are needed to determine long-term effects of DASH in CKD.

Total deviation index (TDI) captures a prespecified quantile of the absolute deviation of paired observations from raters, observers, methods, assays, instruments, etc. We compare the performance of TDI using nonparametric quantile regression to the TDI assuming normality (Lin, 2000). This simulation study considers three distributions: normal, Poisson, and uniform at quantile levels of 0.8 and 0.9 for cases with and without contamination. Study endpoints include the bias of TDI estimates (compared with their respective theoretical values), standard error of TDI estimates (compared with their true simulated standard errors), and test size (compared with 0.05), and power. Nonparametric TDI using quantile regression, although it slightly underestimates and delivers slightly less power for data without contamination, works satisfactorily under all simulated cases even for moderate (say, ≥40) sample sizes. The performance of the TDI based on a quantile of 0.8 is in general superior to that of 0.9. The performances of nonparametric and parametric TDI methods are compared with a real data example. Nonparametric TDI can be very useful when the underlying distribution on the difference is not normal, especially when it has a heavy tail.

There has been substantial statistical literature in the last several decades on assessing agreement, and coverage probability approach was selected as a preferred index for assessing and improving measurement agreement in a core laboratory setting. With this approach, a satisfactory agreement is based on pre-specified high satisfactory coverage probability (e.g., 95%), given one pre-specified acceptable difference. In practice, we may want to have quality control on more than one pre-specified differences, or we may simply want to summarize the agreement based on differences up to a maximum acceptable difference. We propose to assess agreement via the coverage probability curve that provides a full spectrum of measurement error at various differences/disagreement. Relative area under the coverage probability curve is proposed for the summary of overall agreement, and this new summary index can be used for comparison of different intra-methods or inter-methods/labs/observers' agreement. Simulation studies and a blood pressure example are used for illustration of the methodology. Copyright © 2016 John Wiley & Sons, Ltd.

HLA-A*33:01 is strongly associated with drug-induced liver injury (DILI) due to terbinafine and several other unrelated compounds

INTRODUCTION: Drug-induced liver injury (DILI) is a diagnosis of exclusion, and it can be challenging to adjudicate when there are multiple comorbidities and concomitant medications. In this study, we tested the hypothesis that comorbidity burden impacts the causality adjudication in patients with suspected DILI. METHODS: We studied consecutive patients with suspected DILI enrolled in the Drug-Induced Liver Injury Network Prospective Study at 2 centers between 2003 and 2017. The comorbidity burden at presentation was determined using the Charlson Comorbidity Index (CCI). We analyzed the association between significant comorbidity (CCI > 75th percentile) and (i) the adjudication of DILI by expert consensus as definite, highly likely, or probable (high-confidence DILI) and (ii) the Roussel Uclaf Causality Assessment Method (RUCAM) scores. RESULTS: Our cohort consisted of 551 patients who were classified as “no comorbidity” (54%, CCI = 0), “mild comorbidity” (29%, CCI = 1 or 2), and “significant comorbidity” (17%, CCI > 2). The probability of high-confidence DILI was significantly lower in patients with significant comorbidity compared with those with mild or no comorbidities (67% vs 76% vs 87%, respectively, P < 0.001). The mean RUCAM scores decreased with increasing comorbidity (no comorbidity 6.6 ± 2, mild comorbidity 6 ± 2.4, and significant comorbidity 5.6 ± 2.7, P < 0.001). In the multiple logistic regression, significant comorbidity had an independent inverse relationship with DILI (odds ratio: 0.37, 95% confidence interval: 0.2–0.69, P = 0.001). DISCUSSION: Higher comorbidity burden impacts the causality assessment in patients with suspected DILI. Further studies are needed to investigate the utility of comorbidity burden as a variable in the DILI causality instruments.

Drug-induced liver injury can lead to changes of the biliary tree that resemble sclerosing cholangitis. These changes can be seen on magnetic resonance cholangiopancreatography. Idiosyncratic drug-induced liver injury (DILI) has a variable presentation including cholestatic liver injury,1 in which case magnetic resonance imaging (MRI) is often performed to exclude pancreaticobiliary causes of obstruction. Sclerosing cholangitis (SC)-like changes on imaging have been described anecdotally with DILI.2,3 A recent study of 25 consecutive, unselected DILI patients found that 10% had SC-like changes on magnetic resonance cholangiopancreatography (MRCP).4 The aim of the current study was to identify the clinical features of patients enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) prospective study who had SC-like changes on MRCP.

Background & Aims Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. In this study we aimed to describe the presenting features and outcomes of patients with terbinafine hepatotoxicity and to investigate the role of human leukocyte antigen (HLA)-A*33:01. Methods Consecutive high causality cases of terbinafine hepatotoxicity enrolled into the Drug Induced Liver Injury Network were reviewed. DNA samples underwent high-resolution confirmatory HLA sequencing using the Ilumina MiSeq platform. Results All 15 patients with terbinafine hepatotoxicity were more than 40 years old (median = 57 years), 53% were female and the median latency to onset was 38 days (range 24 to 114 days). At the onset of drug-induced liver injury, 80% were jaundiced, median serum alanine aminotransferase was 448 U/L and alkaline phosphatase was 333 U/L. One individual required liver transplantation for acute liver failure during follow-up, and 7 of the 13 (54%) remaining individuals had ongoing liver injury at 6 months, with 4 demonstrating persistently abnormal liver biochemistries at month 24. High-resolution HLA genotyping confirmed that 10 of the 11 (91%) European ancestry participants were carriers of the HLA-A*33:01, B*14:02, C*08:02 haplotype, which has a carrier frequency of 1.6% in European Ancestry population controls. One African American patient was also an HLA-A*33:01 carrier while 2 East Asian patients were carriers of a similar HLA type: A*33:03. Molecular docking studies indicated that terbinafine may interact with HLA-A*33:01 and A*33:03. Conclusions Patients with terbinafine hepatotoxicity most commonly present with a mixed or cholestatic liver injury profile and frequently have residual evidence of chronic cholestatic injury. A strong genetic association of HLA-A*33:01 with terbinafine drug-induced liver injury was confirmed amongst Caucasians. Lay summary A locus in the human leukocyte antigen gene (HLA-A*33:01, B*14:02, C*08:02) was significantly overrepresented in Caucasian and African American patients with liver injury attributed to the antifungal medication, terbinafine. These data along with the molecular docking studies demonstrate that this genetic polymorphism is a plausible risk factor for developing terbinafine hepatotoxicity and could be used in the future to help doctors make a diagnosis more rapidly and confidently.

Background Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction. Methods and Results In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, ≤35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n=8], 0.005; cohort 2 [n=8], 0.05; and cohort 3 [n=8], 0.25 mg·kg −1 ·h −1 ) or placebo control (n=12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid- and end-infusion and 6-, 8-, 12- and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (−18 mL; P =0.009) and end-systolic volume (−14 mL; P =0.005) occurred at end infusion in the highest dose cohort. Conclusions This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose–effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02388464.

Planned interventions and/or natural conditions often effect change on an ordinal categorical outcome (e.g., symptom severity). In such scenarios, it is sometimes desirable to assign a priori scores to observed changes in status, typically giving higher weight to changes of greater magnitude. We define change indices for such data based upon a multinomial model for each row of a c × c table, where the rows represent the baseline status categories. We distinguish an index designed to assess conditional changes within each baseline category from two others designed to capture overall change. One of these overall indices measures expected change across a target population. The other is scaled to capture the proportion of total possible change in the direction indicated by the data, so that it ranges from −1 (when all subjects finish in the least favorable category) to +1 (when all finish in the most favorable category). The conditional assessment of change can be informative regardless of how subjects are sampled into the baseline categories. In contrast, the overall indices become relevant when subjects are randomly sampled at baseline from the target population of interest, or when the investigator is able to make certain assumptions about the baseline status distribution in that population. We use a Dirichlet-multinomial model to obtain Bayesian credible intervals for the conditional change index that exhibit favorable small-sample frequentist properties. Simulation studies illustrate the methods, and we apply them to examples involving changes in ordinal responses for studies of sleep deprivation and activities of daily living. Copyright © 2015 John Wiley & Sons, Ltd.

Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05±55.48m in the immediate intervention group and decreased a mean 11.45±49.46m in the wait list control group (p=0.443). The hemoglobin increased a mean 0.39±0.46g/dL in the immediate intervention group and declined a mean 0.39±0.85g/dL in the wait list control group (p=0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.

While racial variation in ambulatory blood pressure (BP) is known, patterns of diurnal dipping in the context of diabetic kidney disease have not been well defined. The authors sought to determine the association of race with nocturnal dipping status among participants with diabetic kidney disease enrolled in the STOP-DKD (Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease) trial. The primary outcome was nocturnal dipping—percent decrease in average systolic BP from wake to sleep—with categories defined as reverse dippers (decrease

Fenofibrate is a commonly used hypolipidemic associated with rare instances of hepatotoxicity, and routine liver biochemistry monitoring is recommended. The aim of this study is to describe the presenting clinical features, liver histopathology, and outcomes of 7 cases of acute liver injury associated with fenofibrate. All cases of definite, very likely, and probable drug-induced liver injury (DILI) attributed to fenofibrate enrolled in the DILI Network study between 2004 and 2015 were reviewed. Among 1229 patients with confirmed DILI, 7 cases (0.6%) were attributed to fenofibrate. The median age was 43 (range 37–61) years, and latency to onset was short (5–8 weeks) in 4 patients but more prolonged (18–56 weeks) in the rest. Laboratory results at presentation showed hepatocellular, mixed, and cholestatic injury, but 6 cases presented with jaundice. No patient had undergone routine monitoring. Four patients required hospitalization and 2 in whom drug discontinuation was delayed had a severe outcome, 1 undergoing liver transplantation, and 1 developing chronic injury and death. Liver biopsy was available in 4 patients and showed diverse injury patterns. Genetic studies showed the presence of the rare HLA-A*33:01 in 3 patients (43 vs. 1% in control populations). The causality scores were highly likely in 5 and probable in 2. Liver injury after fenofibrate exposure occurs with variable latency, enzyme elevation, and histology. Although most cases are self-limited, severe injury and mortality can occur, particularly if drug withdrawal is delayed. Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation.