Background: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. Methods: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. Results: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-467 % (27 %), 95 %CI: -521 % to -412 % vs. -381 % (29 %), 95 %CI: -438 % to -325 %, respectively; LS mean difference=-85 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -320 % (28 %), 95 %CI: -375 % to -265 % vs. -232 % (29 %), 95 %CI: -289 to -175 %; LS mean difference= -88 %; p = 0026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 103-1145, p = 0044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. Conclusions: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

BackgroundThe increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies. Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker). The liver safety of AD04 has never been evaluated in subjects with AUD. The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD.MethodsLiver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling. ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24. Adverse cardiac events, general well-being, and study completion were also assessed.ResultsLow-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin. While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04. Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment.ConclusionsLow-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort. Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD.

A core principle in the pursuit of scientific knowledge is that science is self-correcting and that important results should be replicable. Hypotheses need to be reinforced, adjusted, or rejected when novel results are obtained. Replication of results confirms hypotheses and enhances their integration into scientific practice. In contrast, publication of substantiated and replicated negative findings (i.e., non-significant or opposite findings) can be the basis to reject erroneous hypotheses or develop alternative strategies for investigation. Replication is a problem in all research fields. The Psychology Reproductivity Project reported that only 36% of ‘highly influential’ published research in highly ranked journals were reproduced. Similar to positive data, negative data can be flawed. Errors in a negative data set can be based on methodology, statistics, conceptual defects, and flawed peer review. The peer review process has received progressive scrutiny. A large-scale review of the peer review process of manuscripts submitted to the British Medical Journal group indicated that the process could be characterized as inconsistent, inaccurate, and biased. Further analysis indicated that the peer process is easily manipulated, indicative of a failed system, is a major factor behind the lack of replication in science (acceptance of flawed manuscripts), suppresses opposing scientific evidence and views, and causes gaps in and lack of growth of science. Complicating the integrity of scientific publication is the role of Editors/Researchers. Ethical guidelines exist for major publishing houses about editorial ethics, behavior, and practice.

Abstract This 6-month, double-blind, randomized, Phase-3 clinical trial in Alcohol Use Disorder (AUD; n = 303) tested ondansetron 0.33 mg/twice daily (AD04) vs placebo in reducing the Percentage of Heavy Drinking Days (PHDD) among a genetic subgroup with variations at the serotonin transporter and 5-HT3A/5-HT-3B receptors who consumed < 10 Standard Drinks/Drinking Day (DDD) (heavy drinkers) or ≥ 10 DDD (very heavy drinkers). At Month 6, the least square (LS) mean change in PHDD from baseline was 8.5% greater in the heavy drinkers AD04 group compared with placebo (LS mean (SD): -46.7% (2.7%), 95%CI: -52.1% to -41.2% vs. -38.1% (2.9%), 95%CI: -43.8% to -32.5%; p = 0.03) with lower effect (LS mean difference: 7.0%, p = 0.07) for Months 5 and 6 combined. At Month 6, for the total AD04 group compared with the placebo group, heavy drinkers had a better quality of life (OR = 3.4, 95% CI: 1.03–11.45, p = 0.04), fewer AUD symptoms (Mild: AD04 group 33% vs. placebo group 39%; Severe: AD04 group 10% vs. placebo group 24%) (p = 0.05), and similar adverse event profiles. No treatment-related effects differentiated AD04 and placebo in very heavy drinkers. This study showed AD04’s promise as a precision medicine treatment for heavy drinkers with a specific genetic profile.

Abstract Genetic predisposition may determine treatment response in alcohol use disorder (AUD). This 6-month, double-blind, randomized trial assessed ondansetron (0.33 mg twice daily; AD04) in genotype-specific AUD subjects stratified by drinking endophenotype (<10 (‘heavy’) or ≥10 (‘severe’) drinks per drinking day). In heavy drinkers, at study end (Month 6), the least-squares (LS) mean change in percentage of heavy drinking days from baseline was 8.5% greater with AD04 vs. placebo treatment (LS mean (standard deviation): -46.7% (2.7%) vs. -38.1% (2.9%); p<0.03), with a non-significant effect (LS mean difference: 7.0%, p=0.07) for Months 5 and 6 combined. AD04 vs. placebo treatment increased quality of life (odds ratio=3.4, 95% Confidence Interval: 1.03-11.45; p=0.04) and reduced AUD symptoms (mild symptoms: 33% vs. 39%; severe symptoms: 10% vs. 24%; p=0.05). AD04 had a similar adverse events profile to placebo. ADO4 showed promise as a precision medicine treatment for genotype-specific heavy drinkers.

BACKGROUND:The serotonin transporter (SERT) mRNA was previously reported to be a quantitative and pathophysiology-based biomarker of heavy drinking in 5HTTLPR:LL genotype-carriers treated with ondansetron. Here, we validated the potential use of SERT mRNA for quantitative prediction of recent alcohol consumption (in the absence of treatment) and compared it with the known biomarkers ethyl glucuronide (EtG) and ethyl sulfate (EtS).METHODS:Binge drinking men and women of European ancestry aged 21 to 65 years were enrolled in a 12-day, in-patient, randomized, double-blind, crossover study, where they were administered three beverage doses (placebo, 0.5 g/kg [0.4 g/kg] ethanol, and 1 g/kg [0.9 g/kg] ethanol for men [women]) individually in three 4-day periods (experiments), separated by minimum 7-day washout period. Diet, sleep, and physical activity were controlled throughout the inpatient experiments. Twenty-nine participants were randomized to receive beverage doses counterbalancing the sequence of treatment and gender within subgroups stratified by SERT genotypes 5HTTLPR:LL+rs25531:AA (LA LA ) versus 5HTTLPR:LS/SS. Peripheral venous blood was collected daily for (1) quantification of SERT mRNA (the primary outcome measure) using qRT-PCR and (2) plasma EtG and EtS levels using tandem mass-spectrometry.RESULTS:The association between administered beverage dose and SERT mRNA from completers of at least one 4-day experiment (N = 18) assessed by a linear mixed model was not statistically significant. Significant positive associations were found with beverage dose and plasma EtG, EtS and EtG/EtS ratio (β = 5.8, SE = 1.2, p < 0.0001; β = 1.3, SE = 0.6, p = 0.023; and β = 3.0, SE = 0.7, p < 0.0001, respectively; the C-statistics for discriminating outcomes were 0.97, 0.8, and 0.92, respectively). Additionally, we observed a sequence effect with a greater placebo effect on SERT mRNA when it was administered during the first experiment (p = 0.0009), but not on EtG/EtS measures.CONCLUSION:The findings do not validate the use of SERT as a biomarker of heavy drinking. Larger and more innovative studies addressing the effects of placebo, race, gender, and response to treatment with serotonergic agents are needed to fully assess the utility of SERT as a biomarker of heavy and binge drinking.

Abstract This 6-month, double-blind, randomized, Phase-3 clinical trial of individuals with Alcohol Use Disorder (AUD) assessed the efficacy of ondansetron 0.33 mg/twice daily (AD04) vs placebo at reducing the Percentage of Heavy Drinking Days (PHDD) among a genetic subgroup with variations at the serotonin transporter and 5-HT3A/5-HT-3B receptors who consumed <10 Standard Drinks/Drinking Day (DDD) (heavy drinkers) or ≥10 DDD (very heavy drinkers) at baseline. At Month 6, the least square (LS) mean change in PHDD from baseline was 8.5% greater in the AD04 group compared with placebo (LS mean (SD): -46.7% (2.7%), 95%CI: -52.1% to -41.2% vs. -38.1% (2.9%), 95%CI: -43.8% to -32.5%; p=0.03) with an almost significant effect (LS mean difference: 7.0%, p=0.07) for Months 5 and 6 combined. At Month 6, for the ADO4 group compared with the placebo group, heavy drinkers had improved psychosocial function (OR=3.4, 95% CI: 1.03-11.45, p=0.04), and fewer AUD symptoms (Mild: AD04 group 33% vs. placebo group 39%; Severe: AD04 group 10% vs. placebo group 24%) (p=0.05). This study showed promise for AD04 as a precision medicine treatment for heavy drinkers with a genetic subtype of AUD.

Background: Cocaine use disorder (CUD) has significant consequences and there remain no FDA-approved pharmacotherapies. Ondansetron is an indirect dopaminergic modulator that has shown efficacy in alcohol use disorder, particularly in phenotypic and genotypic subgroups, and was found to be efficacious in a pilot dosefinding trial for CUD. Methods: One-hundred eight (108) adults with CUD were randomized to ondansetron 4 mg twice daily or placebo for 9 weeks and assessed up to thrice weekly to evaluate self-reported cocaine use and urine benzoylecgonine. Participants received cognitive-behavioral therapy and brief behavioral compliance enhancement therapy. Consenting participants (N = 79) provided blood samples for exploratory pharmacogenetic analyses. Results: Participants in both arms reduced cocaine use over time, but there was no statistically significant difference on percentage of cocaine-free days (PCFD; p = 0.972) or percentage of cocaine-free urine samples (PCFU; p = 0.909). Participants with early-onset CUD had greater improvement regardless of study arm (p = 0.002). Post hoc pharmacogenetic analyses demonstrated an interaction effect between treatment and rs1176713 SNP on PCFU in the total sample (p = 0.040) and African ancestry subset (p = 0.03). Constipation, fatigue, and somnolence were more common among ondansetron-treated participants (Fisher exact p < 0.05). Those who developed constipation were mostly rs1176713:GG carriers (Fisher exact p = 0.029). Conclusions: Ondansetron did not demonstrate efficacy in the treatment of CUD. However, these preliminary results suggest a genotype-based variance in response to ondansetron in African ancestry individuals with CUD. Further studies are needed to validate findings for developing a personalized genomic approach for CUD treatment in racially and ethnically diverse populations.

Background There is substantial evidence for a cumulative dose-related response to ionizing radiation in the form of cancer development years after initial exposure. Therefore, this study focused on effective dose, a quantity with direct correlations to biologic risk from dental x-ray exposures. Objective The purpose of this study was to measure doses and to calculate the effective doses (E) resulting from exposure parameters that are used for stationary intraoral tomosynthesis (s-IOT) and conventional imaging for adult posterior bitewing examinations of the dentition. Additionally, this study sought to evaluate the effect of sensor attenuation on patient dose. Materials and Methods To meet these aims, a human tissue equivalent adult phantom and optically stimulated luminescent (Landauer, Inc., Glenwood, IL) dosimeters were used to measure dose produced during simulated posterior bitewing examinations (n = 4). Optically stimulated luminescent dosimeters were used to measure x-ray dose at 24 head and neck tissue/organ sites of interest. Dosimetry was acquired by using a tissue equivalent phantom simulating the anatomy of an average adult male (AtomMax Model 711 HN,CIRS Inc., Norfolk, VA). Exposure parameters used were 70 kV/7 mA (0.7 mAs) and 0.12 mAs for s-IOT and conventional (KaVo FOCUS, Charlotte, NC), respectively. Analysis of variance (ANOVA) and Tukey’s HSD (“honest significant difference”) statistics on dose were utilized to demonstrate significant data relationships. Results Tabled 1 Effective dose by modality (μSv) Modality Dose (μSv) Rectangular Conventional with Sensor 1.1 Rectangular Conventional without sensor 4.6 s-IOT with sensor 5.9 s-IOT without sensor 11.9 Circular Conventional with sensor 8.2 Circular Conventional without sensor 15.7 Open table in a new tab Sensor-present doses were significantly lower than sensor-absent for all modalities (P = .0001). Significant differences in E were found for all modality combinations with the exception of s-IOT sensor-present modalities vs conventional rectangular sensor-absent modalities (P = .0482). Discussion Unadjusted s-IOT dose was 26% less than conventional-circular exposures and 61% greater than conventional-rectangular for sensor-absent exposures. Unadjusted sensor-present s-IOT dose was 28% less than conventional-circular exposures and 81% greater than conventional-rectangular exposures. Despite a 4-fold increase in mAs for s-IOT imaging compared with conventional imaging, E from s-IOT imaging was at least 26% less than the current most commonly implemented bitewing technique, conventional-circular, while providing substantially greater diagnostic yield in the form of 3-dimensional (3-D) information. There is substantial evidence for a cumulative dose-related response to ionizing radiation in the form of cancer development years after initial exposure. Therefore, this study focused on effective dose, a quantity with direct correlations to biologic risk from dental x-ray exposures. The purpose of this study was to measure doses and to calculate the effective doses (E) resulting from exposure parameters that are used for stationary intraoral tomosynthesis (s-IOT) and conventional imaging for adult posterior bitewing examinations of the dentition. Additionally, this study sought to evaluate the effect of sensor attenuation on patient dose. To meet these aims, a human tissue equivalent adult phantom and optically stimulated luminescent (Landauer, Inc., Glenwood, IL) dosimeters were used to measure dose produced during simulated posterior bitewing examinations (n = 4). Optically stimulated luminescent dosimeters were used to measure x-ray dose at 24 head and neck tissue/organ sites of interest. Dosimetry was acquired by using a tissue equivalent phantom simulating the anatomy of an average adult male (AtomMax Model 711 HN,CIRS Inc., Norfolk, VA). Exposure parameters used were 70 kV/7 mA (0.7 mAs) and 0.12 mAs for s-IOT and conventional (KaVo FOCUS, Charlotte, NC), respectively. Analysis of variance (ANOVA) and Tukey’s HSD (“honest significant difference”) statistics on dose were utilized to demonstrate significant data relationships. Sensor-present doses were significantly lower than sensor-absent for all modalities (P = .0001). Significant differences in E were found for all modality combinations with the exception of s-IOT sensor-present modalities vs conventional rectangular sensor-absent modalities (P = .0482). Unadjusted s-IOT dose was 26% less than conventional-circular exposures and 61% greater than conventional-rectangular for sensor-absent exposures. Unadjusted sensor-present s-IOT dose was 28% less than conventional-circular exposures and 81% greater than conventional-rectangular exposures. Despite a 4-fold increase in mAs for s-IOT imaging compared with conventional imaging, E from s-IOT imaging was at least 26% less than the current most commonly implemented bitewing technique, conventional-circular, while providing substantially greater diagnostic yield in the form of 3-dimensional (3-D) information.

Background There is substantial evidence for a cumulative dose-related response to ionizing radiation in the form of cancer development years after initial exposure. Therefore, this study focused on effective dose (E), a quantity with direct correlations to biologic risk from dental x-ray exposures. Objectives The purpose of this study was to measure doses and calculate (E) from adult full-mouth examinations (FMXs) by using handheld and conventional wall-mounted x-ray sources with both circular and rectangular collimation (RC). Materials and Methods A human tissue-equivalent phantom and optically stimulated luminescent dosimeters were used to measure dose from simulated FMXs (n = 18) at 24 head/neck tissue sites. The parameters were 70 kV/7 mA (0.84 mAs and 1.34 mAs) for Conventional Circular and RC handheld device; 60 kV/2.5 mA (2.16 mAs) for NOMAD Circular and RC handheld device; and 60 kV/2.0 mA (1.98 mAs) for Xray2 Go Circular (XTG) handheld device. Analysis of variance (ANOVA) and Tukey’s HSD (“honest significant difference”) statistics demonstrated significant relationships. Results The FMX E (µSv) values were: NOMAD RC (6.9); XTG (16.7); NOMAD Circular (17.4); and Conventional Circular (26.3). For circular techniques, the handheld device E was significantly lower than the conventional unit for both devices (P < .0001). With RC, E was significantly lower than all circular techniques (P < .0001). Significant differences in E were found for all modality combinations except NOMAD Circular and XTG (P = .8329). Operator groin exposure was significantly higher (60%–90%) than thyroid, chest, and trigger hand exposures, which were indistinguishable from ambient background levels, for all handheld modalities (P < .0001). Discussion Handheld device E was at least 34% less than conventional circular and as much as 74% less with the use of RC. Operator exposure to the groin can increase significantly from overangulating the handheld sources; however, the addition of RC can reduce this exposure by as much as 76%. There is substantial evidence for a cumulative dose-related response to ionizing radiation in the form of cancer development years after initial exposure. Therefore, this study focused on effective dose (E), a quantity with direct correlations to biologic risk from dental x-ray exposures. The purpose of this study was to measure doses and calculate (E) from adult full-mouth examinations (FMXs) by using handheld and conventional wall-mounted x-ray sources with both circular and rectangular collimation (RC). A human tissue-equivalent phantom and optically stimulated luminescent dosimeters were used to measure dose from simulated FMXs (n = 18) at 24 head/neck tissue sites. The parameters were 70 kV/7 mA (0.84 mAs and 1.34 mAs) for Conventional Circular and RC handheld device; 60 kV/2.5 mA (2.16 mAs) for NOMAD Circular and RC handheld device; and 60 kV/2.0 mA (1.98 mAs) for Xray2 Go Circular (XTG) handheld device. Analysis of variance (ANOVA) and Tukey’s HSD (“honest significant difference”) statistics demonstrated significant relationships. The FMX E (µSv) values were: NOMAD RC (6.9); XTG (16.7); NOMAD Circular (17.4); and Conventional Circular (26.3). For circular techniques, the handheld device E was significantly lower than the conventional unit for both devices (P < .0001). With RC, E was significantly lower than all circular techniques (P < .0001). Significant differences in E were found for all modality combinations except NOMAD Circular and XTG (P = .8329). Operator groin exposure was significantly higher (60%–90%) than thyroid, chest, and trigger hand exposures, which were indistinguishable from ambient background levels, for all handheld modalities (P < .0001). Handheld device E was at least 34% less than conventional circular and as much as 74% less with the use of RC. Operator exposure to the groin can increase significantly from overangulating the handheld sources; however, the addition of RC can reduce this exposure by as much as 76%.

Importance The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use. Objective To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes. Design, Setting, and Participants Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV–categorized alcohol dependence. Main Outcomes and Measures Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h). Results Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, −0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, −0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, −0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, −0.020 to 0.303]; varenicline, 0.146 [95% CI, −0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, −0.021 to 0.302]; varenicline, 0.232 [95% CI, −0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]). Conclusions and Relevance WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days. Trial Registration ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925

Zero-inflated nonnegative continuous (or semicontinuous) data arise frequently in biomedical, economical, and ecological studies. Examples include substance abuse, medical costs, medical care utilization, biomarkers (e.g., CD4 cell counts, coronary artery calcium scores), single cell gene expression rates, and (relative) abundance of microbiome. Such data are often characterized by the presence of a large portion of zero values and positive continuous values that are skewed to the right and heteroscedastic. Both of these features suggest that no simple parametric distribution may be suitable for modeling such type of outcomes. In this paper, we review statistical methods for analyzing zero-inflated nonnegative outcome data. We will start with the cross-sectional setting, discussing ways to separate zero and positive values and introducing flexible models to characterize right skewness and heteroscedasticity in the positive values. We will then present models of correlated zero-inflated nonnegative continuous data, using random effects to tackle the correlation on repeated measures from the same subject and that across different parts of the model. We will also discuss expansion to related topics, for example, zero-inflated count and survival data, nonlinear covariate effects, and joint models of longitudinal zero-inflated nonnegative continuous data and survival. Finally, we will present applications to three real datasets (i.e., microbiome, medical costs, and alcohol drinking) to illustrate these methods. Example code will be provided to facilitate applications of these methods.

Aims The aim of this study was to quantify the risk of developing cancer from the exposure to radiation associated with surgery to correct limb deformities in children. Patients and Methods A total of 35 children were studied. There were 19 girls and 16 boys. Their mean age was 11.9 years (2 to 18) at the time of surgery. Details of the radiological examinations were recorded during gradual correction using a Taylor Spatial Frame. The dose area product for each radiograph was obtained from the Computerised Radiology Information System database. The effective dose in millisieverts (mSv) was calculated using conversion coefficients for the anatomical area. The lifetime risk of developing cancer was calculated using government-approved Health Protection Agency reports, accounting for the age and gender of the child. Results Correction was undertaken in five femurs, 18 tibiae, and 12 feet. The median duration of treatment was 45 months (11 to 118). The mean effective dose was 0.31 mSv (0.05 to 0.64) for the femur, 0.29 mSv (0.01 to 0.97) for the tibia, and 0.027 mSv (0.001 to 0.161) for the foot. The cumulative exposure gave ‘negligible’ risk in 26 children and ‘minimal’ risk in nine children, according to Public Health England categories. These results are below the mean annual background radiation in the United Kingdom. Conclusion The lifetime attributable risk of developing cancer from repeated exposure to radiation was negligible or minimal in all children. This is the first study to quantify the exposure to radiation from serial radiographs in children with limb deformities who are treated surgically using circular external fixation, linking this to the risk of developing cancer. Cite this article: Bone Joint J 2019;101-B:241–245.

Random effects two-part models have been applied to longitudinal studies for zero-inflated (or semi-continuous) data, characterized by a large portion of zero values and continuous non-zero (positive) values. Examples include monthly medical costs, daily alcohol drinks, relative abundance of microbiome, etc. With the advance of information technology for data collection and storage, the number of variables available to researchers can be rather large in such studies. To avoid curse of dimensionality and facilitate decision making, it is critically important to select covariates that are truly related to the outcome. However, owing to its intricate nature, there is not yet a satisfactory variable selection method available for such sophisticated models. In this paper, we seek a feasible way of conducting variable selection for random effects two-part models on the basis of the recently proposed "minimum information criterion" (MIC) method. We demonstrate that the MIC formulation leads to a reasonable formulation of sparse estimation, which can be conveniently solved with SAS Proc NLMIXED. The performance of our approach is evaluated through simulation, and an application to a longitudinal alcohol dependence study is provided.

THIS INTERESTING PAPER by Witkiewitz and colleagues (2017) calls for the need to create a more comprehensive scale to acknowledge and measure the naturally fluctuating levels of drinking among patients. As such, there is a dire need to unify, under a common instrument, a clinically meaningful end point measure to determine the efficacy of treatment for alcohol use disorder (AUD) for both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Such a homology would have the advantage that any treatment found to be efficacious in either of these influential and pioneering domains would be applicable to the other. Therefore, potentially thorny issues of a putative therapeutic medicine being found to be efficacious in Europe, only to be rejected for approval in the United States (Zindel and Kranzler, 2014), or vice versa, would be avoided. Furthermore, agreement as to what would constitute a clinically efficacious treatment for AUD would enable scientists, researchers, and clinicians to work from a common platform across the Western world to progress rapidly the development of new medicinal, psychological, and combined treatments.

Alcohol: Clinical and Experimental ResearchVolume 41, Issue 7 p. 1383-1384 Letter to the Editor FDA and EMA Need Homology on Alcohol Outcome Measures—Semper: Simplicitas est purius modum Bankole A. Johnson, Corresponding Author Bankole A. Johnson bjohnson@som.umaryland.edu orcid.org/0000-0002-8901-6177 Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MarylandReprint requests: Bankole A. Johnson, DSc, MD, PhD, Department of Psychiatry, University of Maryland School of Medicine, 110 South Paca Street, Rm 4N140, Baltimore, MD 21201; Tel.: 410-328-6735; Fax: 410-328-3693; E-mail: bjohnson@som.umaryland.eduSearch for more papers by this author Bankole A. Johnson, Corresponding Author Bankole A. Johnson bjohnson@som.umaryland.edu orcid.org/0000-0002-8901-6177 Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MarylandReprint requests: Bankole A. Johnson, DSc, MD, PhD, Department of Psychiatry, University of Maryland School of Medicine, 110 South Paca Street, Rm 4N140, Baltimore, MD 21201; Tel.: 410-328-6735; Fax: 410-328-3693; E-mail: bjohnson@som.umaryland.eduSearch for more papers by this author First published: 04 May 2017 https://doi.org/10.1111/acer.13412Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume41, Issue7July 2017Pages 1383-1384 RelatedInformation