Author: Nevin Manimala

Stat Med. 2021 Mar 26. doi: 10.1002/sim.8946. Online ahead of print.

ABSTRACT

Given the Food and Drug Administration’s (FDA’s) acceptance of master protocol designs in recent guidance documents, the oncology field is rapidly moving to address the paradigm shift to molecular subtype focused studies. Identifying new “marker-based” treatments requires new methodologies to address the growing demand to conduct clinical trials in smaller molecular subpopulations, identify effective treatment and marker interactions, and control for false positives. We introduce our methodology, Hierarchical Bayesian Clustering Design of Multiple Biomarker Subgroups (HCOMBS), a two-stage umbrella Phase II design with effect size clustering and information borrowing across multiple biomarker-treatment pairs. HCOMBS was designed to reduce required sample size, differentiate between varying effect sizes, and control for operating characteristics in the multi-arm setting. When compared to independently applied Simon’s Optimal two-stage design, we showed through simulations that HCOMBS required less participants per treatment arm with a well-controlled family-wise error rate and desirable marginal power. Additionally, HCOMBS features a statistical approach that simultaneously conducts clustering and hypothesis testing in one step. We also applied the proposed design on the alliance brain metastases umbrella trial.

PMID:33772843 | DOI:10.1002/sim.8946

Br J Clin Pharmacol. 2021 Mar 27. doi: 10.1111/bcp.14839. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the association between antipsychotic use in pregnancy and the risk of congenital malformations in children.

DATA SOURCES: Searches of PubMed, EMBASE, PsycINFO and Cochrane Library were conducted from inception to 06 Jan 2020 using keywords: antipsychotics, pregnancy, pregnancy complication and congenital abnormalities.

STUDY SELECTION: Of 38 reports initially identified as being of potential interest, 13 studies met our inclusion criteria: English observational studies that examined the association between gestational antipsychotic use and congenital malformations in children.

DATA EXTRACTION: Data were extracted independently by two investigators including the publication year, study site, study period, data source, study design, sample size, medication exposure, exposure period and pregnancy definition, exposure as well as outcome ascertainment, selection of study and comparison group, confounding adjustment, statistical analysis, and method of linkage between mother and children. Risk estimates were pooled using a random-effect model and the I² statistic was used to evaluate the degree of heterogeneity.

RESULTS: 13 studies met our systematic review inclusion criteria. Six studies with a total of 2,515,272 pregnancy episodes were included in our meta-analysis which provided a pooled adjusted risk ratio of 1.23, 95% confidence interval: 0.96-1.58. The I² result showed moderate heterogeneity between studies (I² =35.2%, p=0.173).

CONCLUSIONS: We did not find strong evidence of an association between prenatal exposure to antipsychotic medications and the risk of congenital malformations in children. We recommend further studies investigate this association, focusing on specific medication classes and dose responses, which would help clinicians decide whether or not to prescribe certain antipsychotics during pregnancy.

PMID:33772841 | DOI:10.1111/bcp.14839

Ophthalmic Physiol Opt. 2021 Mar 27. doi: 10.1111/opo.12807. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the feasibility and repeatability of Lenstar LS 900 biometry measurements in a paediatric population.

METHODS: Children were examined as part of the LIFE Child Study (Leipzig Research Centre for Civilization Diseases), a population-based study in Leipzig, Germany. Altogether, 1917 children, aged from 3.5 to 17.5 years, were assessed with the Haag Streit Lenstar LS 900. Three consecutive measurements of the right eye were analysed for axial length, central corneal thickness, anterior chamber depth, aqueous depth, lens thickness and flat and steep corneal radii. The number of successful measurements and repeatability were evaluated for each parameter and three age bands (3.5 to 6.5 years, 6.5 to 10.5 years and 10.5 to 17.5 years).

RESULTS: Best measurement feasibility was found for axial length and central corneal thickness (91% to 100%), followed by flat and steep corneal radii (86% to 100%), anterior chamber and aqueous depth (76% to 92%) and lens thickness (50% to 81%), with higher numbers for older children. Repeatability values (in mm) were: axial length 0.025 to 0.035; central corneal thickness 0.003 to 0.027; aqueous depth 0.024 to 0.058; anterior chamber 0.024 to 0.054; lens thickness 0.034 to 0.067. An overall trend showed better repeatability for older children, especially for central corneal thickness, aqueous depth and lens thickness.

CONCLUSIONS: For ocular biometry in the paediatric population, axial length, central corneal thickness, flat and steep corneal radii can be measured very reliably even in children from 4 years old onward using the Lenstar LS 900. Lens thickness can be quantified in a limited number of younger children. Repeatability was high for all variables investigated. Repeatability improved with age, reaching adult values in the adolescent age band. Established repeatability limits can be applied in future studies as a quality parameter.

PMID:33772832 | DOI:10.1111/opo.12807

Pharmacotherapy. 2021 Mar 27. doi: 10.1002/phar.2521. Online ahead of print.

ABSTRACT

BACKGROUND: Methadone is associated with QT interval prolongation and torsades de pointes. Expert panel recommendations advocate a pre-methadone electrocardiogram (ECG) and another ECG at 30 days of therapy in patients with risk factors. Some recommend a pre-methadone ECG and routine ECG monitoring in all methadone patients, but this is controversial due to the resources required. Availability of a convenient, less resource-intensive method of ECG monitoring for patients taking methadone is desirable.

OBJECTIVES: Assess the accuracy of a handheld smartphone ECG (iECG) for QT measurement in patients on maintenance methadone therapy in an urban opioid treatment program.

METHODS: Patients (n=115) in normal sinus rhythm who were on steady-state maintenance methadone therapy underwent a simultaneous 12-lead ECG and a single-lead iECG. The first three QT and RR intervals from lead II of the 12-lead ECG and simulated lead I from the iECG were compared using the Bland-Altman analysis of measurement agreement.

RESULTS: Mean [± standard deviation) age was 34±11 years; 71% were female, 75% were white. Compared to the 12-lead ECG, the iECG was associated with a QTc bias of – 0.14 ms (SD=12 ms, 95% CI = -2.4 to 2.1 ms). The absolute mean difference in QTc between the two methods was 9.5±7.1 ms. For identification of patients with methadone-associated QTc prolongation, the iECG performed moderately well [c-statistic 0.97 (95% CI 0.91-0.99); sensitivity and specificity 75% (95% CI 43-95%) and 99% (95% CI 94-99%), respectively]. The positive and negative likelihood ratios of the iECG for identifying patients with methadone-associated QTc prolongation were 77.25 (95% CI 10.69 to 558.18) and 0.25 (95% CI 0.09 to 0.67), respectively, while the positive and negative predictive values were 90% (95% CI 56-99%) and 97% (95% CI 92-99%), respectively. The accuracy of the iECG for identifying patients with QTc prolongation was 97% (95% CI 91-99%).

CONCLUSION: A handheld smartphone ECG is accurate for QT interval measurement in patients taking maintenance methadone therapy, and its performance is moderately good for identifying patients with methadone-associated QTc prolongation.

PMID:33772822 | DOI:10.1002/phar.2521

Med Phys. 2021 Mar 26. doi: 10.1002/mp.14865. Online ahead of print.

ABSTRACT

PURPOSE: Contouring variation is one of the largest systematic uncertainties in radiotherapy, yet its effect on clinical outcome has never been analysed quantitatively. We propose a novel, robust methodology to locally quantify target contour variation in a large patient cohort and find where this variation correlates with treatment outcome. We demonstrate its use on biochemical recurrence for prostate cancer patients.

METHOD: We propose to compare each patient’s target contours to a consistent and unbiased reference. This reference was created by auto-contouring each patient’s target using an externally trained deep learning algorithm. Local contour deviation measured from the reference to the manual contour were projected to a common frame of reference, creating contour deviation maps for each patient. By stacking the contour deviation maps, time to event was modelled pixel-wise using a multivariate Cox proportional hazards model (CPHM). Hazard ratio (HR) maps for each covariate were created, and regions of significance found using cluster-based permutation testing on the z-statistics. This methodology was applied to Clinical Target Volume (CTV) contours, containing only the prostate gland, from 232 intermediate- and high-risk prostate cancer patients. The reference contours were created using ADMIRE® v3.4 (Elekta AB, Sweden). Local contour deviations were computed in a spherical coordinate frame, where differences between reference and clinical contours were projected in a 2D map corresponding to sampling across the coronal and transverse angles every 3°. Time to biochemical recurrence was modelled using the pixel-wise CPHM analysis accounting for contour deviation, patient age, Gleason score and treated CTV volume.

RESULTS: We successfully applied the proposed methodology to a large patient cohort containing data from 232 patients. In this patient cohort, our analysis highlighted regions where the contour variation was related to biochemical recurrence, producing expected and unexpected results: 1) the interface between prostate-bladder and prostate-seminal vesicle interfaces where increase of the manual contour relative to the reference was related to a reduction of risk of biochemical recurrence by 4-8% per mm and 2) the prostate’s right, anterior and posterior regions where an increase of the manual contour relative to the reference contours was related to an increase of risk of biochemical recurrence by 8-24% per mm.

CONCLUSION: We proposed and successfully applied a novel methodology to explore the correlation between contour variation and treatment outcome. We analysed the effect of contour deviation of the prostate CTV on biochemical recurrence for a cohort of more than 200 prostate cancer patients while taking basic clinical variables into account. Applying this methodology to a larger dataset including additional clinically important covariates and externally validating it can more robustly identify regions where contour variation directly relates to treatment outcome. For example, in the prostate case we use to demonstrate our novel methodology, external validation will help confirm or reject the counter-intuitive results (larger contours resulting in higher risk). Ultimately, the results of this methodology could inform contouring protocols based on actual patient outcomes.

PMID:33772803 | DOI:10.1002/mp.14865

J Dent Educ. 2021 Mar 27. doi: 10.1002/jdd.12599. Online ahead of print.

ABSTRACT

PURPOSE/OBJECTIVES: In light of a movement to eliminate the historical separation of dentistry and medicine to produce more collaborative and knowledgeable clinicians and to improve care, integrated education models are vital. This study aimed to demonstrate the effectiveness of an integrated medical and dental student curriculum at the University of Connecticut. It was hypothesized that a medical and dental student doctoring course within an already combined biomedical curriculum would result in statistically significantly increases in dental student clinical skills performance.

METHODS: Analysis of variance (ANOVA) was utilized for an overall test of scores from 2016 to 2019. When ANOVA indicated significant differences, post hoc pairwise comparisons using Tukey’s adjustment classified pairs that differed significantly. Lastly, a contrast was constructed to test the difference before and after the course’s introduction. A two-sided α of 0.05 was used.

RESULTS: Dental students were assessed on three cases for history taking and master interview rating scale (MIRS) criteria. The mean averages in history taking and MIRS criteria after the implementation of this course increased by 7.81 (SE = 1.83, p < 0.0001) and 11.95 (SE = 1.34, p < 0.0001) for a toothache case, 11.37 (SE = 1.98, p < 0.0001) and 9.84 (SE = 1.35, p < 0.0001) for a loose bridge case, and 12.47 (SE = 1.75, p < 0.0001) and 10.07 (SE = 1.28, p < 0.0001) for a sensitive tooth case.

CONCLUSION: An integrated doctoring course within a combined curriculum at the University of Connecticut Schools of Medicine and Dental Medicine resulted in a statistically significant increase in dental student clinical skills assessment scores, demonstrating this model’s utility.

PMID:33772785 | DOI:10.1002/jdd.12599

J Fish Biol. 2021 Mar 27. doi: 10.1111/jfb.14739. Online ahead of print.

ABSTRACT

Meristic variation among stocks of greater lizardfish Saurida tumbil through the western coasts of the Arabian Gulf and Sea of Oman was examined using meristic characters. Statistical analysis of meristic traits proposed that there is constrained migration of populations of greater lizardfish along the western coast of the Arabian Gulf and Sea of Oman. Overlapping of the two samples from the northern part of the Arabian Gulf (Iraq-Kuwait waters), three samples from the middle region of the Arabian Gulf (Bahrain-Qatar-Saudi Arabia) and two samples from the southern part of the Arabian Gulf/Sea of Oman (United Arab Emirates-Sultanate of Oman) suggested that there are three self-recruiting population in the studied area. Inspection of the role of each meristic trait variable to Canonical discriminant analysis showed that changes among samples appeared to be linked with the pattern of distribution of water temperature and configuration of current in both the Arabian Gulf and Sea of Oman areas. This article is protected by copyright. All rights reserved.

PMID:33772771 | DOI:10.1111/jfb.14739

Eur J Immunol. 2021 Mar 27. doi: 10.1002/eji.202049101. Online ahead of print.

ABSTRACT

Humoral immunity to the Severe Adult Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is not fully understood yet but is a crucial factor of immune protection. The possibility of antibody cross-reactivity between SARS-CoV-2 and other human coronaviruses (HCoVs) would have important implications for immune protection but also for the development of specific diagnostic ELISA tests. Using peptide microarrays, n = 24 patient samples and n = 12 control samples were screened for antibodies against the entire SARS-CoV-2 proteome as well as the Spike (S), Nucleocapsid (N), VME1 (V), R1ab, and Protein 3a (AP3A) of the HCoV strains SARS, MERS, OC43 and 229E. While widespread cross-reactivity was revealed across several immunodominant regions of S and N, IgG binding to several SARS-CoV-2-derived peptides provided statistically significant discrimination between COVID-19 patients and controls. Selected target peptides may serve as capture antigens for future, highly COVID-19-specific diagnostic antibody tests. This article is protected by copyright. All rights reserved.

PMID:33772767 | DOI:10.1002/eji.202049101

J Am Geriatr Soc. 2021 Mar 26. doi: 10.1111/jgs.17137. Online ahead of print.

ABSTRACT

BACKGROUND/OBJECTIVES: Evidence on the effectiveness of inpatient hospital geriatric consultation is scant, and it is unknown whether adherence to specific recommendations will improve care and patient outcomes. This study was conducted to provide insights from a quality improvement project that may help guide further improvements in the effectiveness of these consultations made as a component of a care transitions program (CTP).

DESIGN: Secondary analysis of the implementation of a multicomponent CTP for high-risk hospitalized patients aged 75 and older.

SETTING: A 400-bed community teaching hospital.

PARTICIPANTS: Two hundred and two patients admitted to non-ICU beds who met high-risk criteria.

INTERVENTION: Inpatient comprehensive geriatric consultation including care transition recommendations, telephone and in-person follow-up weekly for 4 weeks after discharge, and collaboration with post-acute organizations and primary care and specialist physicians to implement recommendations.

MEASUREMENTS: Primary outcomes for this analysis was 30-day hospital readmissions and adherence to transition of care recommendations.

RESULTS: The 142 patients with at least one post-discharge visit received 936 care transition recommendations. Overall, 663 (71%) of the 936 care transition recommendations were adhered to (71%). The adherence rate was lower in the 22 patients who were readmitted to the hospital within 30 days (63%) compared to 72% adherence in the 120 patients who were not readmitted. This was not a statistically significant difference, and there were no significant differences in the number and percent adherence in any recommendation category between the two groups.

CONCLUSION: We found adherence to just over two-thirds of care transition recommendations, similar to a small number of other studies. We did not find a relationship between the number of recommendations and adherence to them with 30-day readmissions to the hospital. Future studies of CTPs should consider several strategies may enhance geriatric consultation care transitions recommendations and adherence to them, and improve patient outcomes.

PMID:33772760 | DOI:10.1111/jgs.17137

Clin Pharmacol Ther. 2021 Mar 26. doi: 10.1002/cpt.2240. Online ahead of print.

ABSTRACT

Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. While this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly underrepresented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (1) TdP classifiers require different features in females vs. males; (2) male-based classifiers perform more poorly when applied to female data; (3) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially life-threatening consequences for the female population.

PMID:33772748 | DOI:10.1002/cpt.2240