Category: Statistics

Stat Med. 2025 May;44(10-12):e70124. doi: 10.1002/sim.70124.

ABSTRACT

The MCP-Mod approach by Bretz et al. is commonly applied for dose-response testing and estimation in clinical trials. The MCP part of MCP-Mod was originally developed to detect a dose-response signal using a multiple contrast test, but it is not appropriate to make a specific claim that the drug has a positive effect at an individual dose. In this paper, we extend the MCP-Mod approach to obtain confirmatory p-values for detecting a dose-response signal as well as for the pairwise comparisons of the individual doses against placebo. We apply the closed test principle from Marcus et al. to the optimal contrast tests based on a candidate set of plausible dose-response shapes available at the planning stage of a clinical trial. We show that the contrast coefficients have to be optimized under suitable constraints to guarantee strong Type 1 error rate control at a pre-specified significance level. Motivated by a recent clinical trial, we evaluate the operating characteristics of the proposed methods in a comprehensive simulation study.

PMID:40384574 | DOI:10.1002/sim.70124

J Pineal Res. 2025 Apr;77(3):e70052. doi: 10.1111/jpi.70052.

ABSTRACT

Climate change, specifically high temperatures, can reduce soil moisture and cause hypersaline conditions, which creates an unsustainable agro-production system. Microbial symbionts associated with plants relinquish stressful conditions by producing stress-protecting substances. Melatonin is a signaling and stress-protecting molecule for plants, but is least known for microbial symbionts and their function in stress protection. Here, our study shows that the melatonin-synthesizing Bacillus velezensis EH151 (27.9 ng/mL at 96 h) significantly improved host plant (Glycine max L.) growth, biomass, photosynthesis, and reduced oxidative stress during heat and salinity stress conditions than the non-inculcated control. The EH151 symbiosis enhanced the macronutrient (P, Ca, and K) and reduced Na uptake in shoots during stress conditions. The microbial inoculation significantly expressed the high-affinity K⁺ transporter, MYB transcription factor, Salt Overly Sensitive 1, Na⁺/H⁺ antiporter 2, and heat shock transcription factors in spatio-temporal orders during heat and salinity stress (H&S 1, 3, 10, and 14 h). We observed that microbial strain significantly increased the plant’s endogenous abscisic acid (49.5% in H&S 10 h), jasmonic acid (71% in H&S 10 h), and melatonin biosynthesis (418% in H&S 14 h). Metabolome map of plant defense response showed that EH151 enhanced activation of amino acid metabolism pathways (e.g., glutamate (34%) L-aspartate (82%), glycine (18.5%), and serine (58%) under H&S 14 h compared to non-inoculation). Conversely, the free sugars and organic acids within the central carbon metabolism were significantly activated in non-inoculated combined heat and salinity stress compared to inoculated plants-suggesting lesser defense energy activated for stress tolerance. In conclusion, the current results show promising effects of the microbial abilities of melatonin that can regulate host growth and defense responses. Utilization of beneficial strains like B. velezensis EH151 could be the ideal strategy to improve stress tolerance and overcome the adverse impact of climate-induced abrupt changes.

PMID:40384569 | DOI:10.1111/jpi.70052

Stat Med. 2025 May;44(10-12):e70118. doi: 10.1002/sim.70118.

ABSTRACT

A dose optimization trial in oncology may be performed to compare an approved dose level of a given drug with a reduced dose level, testing the hypothesis that efficacy is maintained whilst reducing side effects and consequently improving adherence and quality-of-life. This is particularly relevant with modern therapeutic agents whose mechanisms of action imply that efficacy may not necessarily be linearly related to the dose. Using a conventional non-inferiority framework leads to large sample sizes that are often unfeasible in the phase IV setting. An alternative is to use a margin of practical non-inferiority, which we define in this paper and show how it can be exploited to justify a sample size. Whilst defining the extent of the margin, researchers also pre-specify the other dimensions of interest, such as receptor occupancy and/or side effects and quality-of-life, that will be used to establish practical non-inferiority if the observed efficacy of the reduced dose level lies within the margin. The comparison of efficacy is based on the observed difference between the reduced and the approved levels, instead of the confidence interval of this difference, leading to a reduction in sample size. The reduction in precision due to the smaller sample size is compensated by formally pre-specifying the additional dimensions to the decision process, allowing a more thorough assessment of the opportunity to reduce a dose in practice, with the many advantages that this may involve.

PMID:40384561 | DOI:10.1002/sim.70118

J Oral Rehabil. 2025 May 19. doi: 10.1111/joor.14011. Online ahead of print.

ABSTRACT

BACKGROUND: Several studies have examined the impact of tooth loss on nutrient intake, yielding mixed results.

OBJECTIVES: This cross-sectional study aimed to investigate the association among the number of teeth present, nutrient intake and food group consumption in Japanese adults with no history of the four major diseases (diabetes, cancer, heart disease and stroke).

METHODS: Data were obtained from the baseline survey of the Japan Multi-Institutional Collaborative Cohort study conducted in the Shizuoka and Daiko areas. Participants completed a self-administered questionnaire on their number of teeth, medical history (diabetes, cancer, heart disease and stroke), education level, employment status and lifestyle factors, such as diet, smoking history and exercise habits. The number of teeth was classified into four groups: 0 teeth, 1-19 teeth, 20-27 teeth and 28-32 teeth.

RESULTS: A total of 8912 individuals included in the analysis had a mean age ± SD of 51.7 ± 9.5 years, with women accounting for 53.6% of the total. In adult men, the number of teeth was negatively associated with the intake of vitamin D, n-3 highly unsaturated fatty acid intake and seafood, while in women, bread consumption was positively associated with the number of teeth.

CONCLUSIONS: These findings suggest that the number of teeth is independently associated with poor nutritional status in Japanese adults with no history of the four major diseases.

PMID:40384543 | DOI:10.1111/joor.14011

Stat Med. 2025 May;44(10-12):e70125. doi: 10.1002/sim.70125.

ABSTRACT

Given the rising complexity and burden of multimorbidity, it is crucial to provide evidence-based support for managing multimorbidity-related clinical outcomes. This study introduces a dynamic network approach to investigate conditional and time-varying interconnections in disease-specific clinical outcomes. Our method effectively tackles the issue of zero inflation, a frequent challenge in medical data that complicates traditional modeling techniques. The theoretical foundations of the proposed approach are rigorously developed and validated through extensive simulations. Using Taiwan’s health administrative claims data from 2000 to 2013, we construct 14 yearly networks that are temporally correlated, featuring 125 nodes that represent different disease conditions. Key network properties, such as connectivity, module, and temporal variation are analyzed. To demonstrate how these networks can inform multimorbidity management, we focus on breast cancer and analyze the relevant network structures. The findings provide valuable clinical insights that enhance the current understanding of multimorbidity. The proposed methods offer promising applications in shaping treatment strategies, optimizing health resource allocation, and informing health policy development in the context of multimorbidity management.

PMID:40384542 | DOI:10.1002/sim.70125

ANZ J Surg. 2025 May 19. doi: 10.1111/ans.70184. Online ahead of print.

ABSTRACT

INTRODUCTION: Limited knowledge exists on how post-graduate surgical coursework programs impact surgical research outputs in Australia. This study evaluated the impact of university-based teaching in research methods and supervisor characteristics on research quality and short-term research output for students undertaking the Master of Surgery (MS) post-graduate coursework degree within Australia.

METHODS: A retrospective cohort analysis of students enrolled in the dissertation for The University of Sydney MS program between 2010 and 2020. Grades for the dissertation and research subjects were extracted from the central university analytics. PubMed and Web of Science were used to determine if the dissertation was published and identify other publications by the students. A Google search was completed to identify supervisor characteristics. Statistical analysis involved logistic regression, multiple linear regression and negative binomial regression.

RESULTS: Three hundred and seventy-nine students were included in this study. Fifty-three percent of the students had an associated publication from their dissertation at a median of 18 months post-enrolment and a median journal impact factor of 2.19. Students averaged 2.1 additional publications (range 0-30) 2 years post-dissertation completion. Students with a distinction/high distinction grade in the dissertation subject or ≥ three journal publications prior were significantly more likely to publish their dissertation (OR 2.26, 95% CI = 1.42-3.61, p < 0.001; OR 3.35, 95% CI = 1.90-5.92, p < 0.001 respectively). Students who received a distinction/high distinction in the research methods subject had 64% more first-author publications within 2 years of finishing the dissertation (95% CI = 1.20-2.23, p = 0.002).

CONCLUSION: Engagement in structured teaching in research methods and prior research experience significantly improve short-term research output amongst early surgical researchers.

PMID:40384532 | DOI:10.1111/ans.70184

Int J Occup Saf Ergon. 2025 May 19:1-8. doi: 10.1080/10803548.2025.2499312. Online ahead of print.

ABSTRACT

Objective. This study aimed to determine the prevalence of enhanced physiologic tremor (EPT) among health personnel and identify common risk factors associated with this condition. Methods. The cross-sectional study was conducted at Benha University Hospital. A total of 535 healthcare professionals (HCPs) were involved in the final analysis. Neurological examinations were conducted under the supervision of the neurology department. Participants were considered to have a tremor according to the Consensus Statement criteria for the diagnosis of tremors. The generalized anxiety disorder assessment, the caffeine consumption questionnaire and the international physical activity questionnaire short-form were used to evaluate anxiety, daily caffeine consumption and physical activity levels, respectively. Results. The prevalence of EPT among HCPs was 5.42%. There was a statistically significant association between EPT and anxiety, smoking, caffeine consumption, sleep deprivation, past psychiatric history, regular exercising, and drug and substance usage. Conclusion. This study identified a high prevalence of EPT among HCPs. Factors associated with EPT include age, sleep deprivation, smoking, caffeine consumption, anxiety and psychiatric history. The findings highlight the need for mental health interventions to mitigate the EPT impact. Addressing stress and promoting well-being among HCPs is crucial for improving their work environment and performance.

PMID:40384531 | DOI:10.1080/10803548.2025.2499312

J Sports Sci. 2025 May 19:1-15. doi: 10.1080/02640414.2025.2502894. Online ahead of print.

ABSTRACT

The study compares three methods of evaluating semi-tethered performance in front crawl swimming using different velocity extraction techniques. Thirty Level 4 swimmers (17 males, 13 females) completed three protocols: Absolute (5 × 25 m, 1-9 kg for males; 1-5 kg for females), Modified (3 × 10 m, 1, 5, 9 kg for males; 1, 3, 5 kg for females) and Velocity-Restricted (device limited to 1 m/s), across three testing sessions, 7 days apart. Absolute and Modified protocols generated load-velocity (LV) and force-velocity (FV) profiles, while Velocity-Restricted produced an FV profile to determine maximal velocity (LV-V₀, FV-V₀), absolute and relative load/force (L₀, F₀, rL₀, rF₀) and slope (S_LV, S_FV). Reliability estimates for the Absolute method: ICC 0.74-0.83, CV% 2.4-9.0% for males; ICC 0.57-0.87, CV% 2.4-11.6% for females. Modified: ICC 0.51-0.85, CV% 2.8-13.7% for males; ICC 0.16-0.80, CV% 2.9-17.1% for females. Velocity-Restricted: ICC 0.50-0.84, CV% 2.6-8.5% for males; ICC 0.10-0.55, CV% 4.2-21.7% for females. FV-V₀ was significantly higher than LV-V₀ (p < 0.001), showing LV and FV outputs are not interchangeable. No statistical differences between Absolute and Modified protocols suggest that the latter (5 m analysis) is a more time-efficient method. Differences in reliability highlight the need for sex-specific considerations when interpreting results.

PMID:40384530 | DOI:10.1080/02640414.2025.2502894

Stat Med. 2025 May;44(10-12):e70126. doi: 10.1002/sim.70126.

ABSTRACT

In clinical trials, principal stratification analysis is commonly employed to address the issue of truncation by death, where a subject dies before the outcome can be measured. However, in practice, many survivor outcomes may remain uncollected or be missing not at random, posing a challenge to standard principal stratification analysis. In this article, we explore the identification, estimation, and bounds of the average treatment effect within a subpopulation of individuals who would potentially survive under both treatment and control conditions. We show that the causal parameter of interest can be identified by introducing a proxy variable that affects the outcome only through the principal strata, while requiring that the treatment variable does not directly affect the missingness mechanism. Subsequently, we propose an approach for estimating causal parameters and derive nonparametric bounds in cases where identification assumptions are violated. We illustrate the performance of the proposed method through simulation studies and a real dataset obtained from a human immunodeficiency virus study.

PMID:40384521 | DOI:10.1002/sim.70126

Pharmacol Res Perspect. 2025 Jun;13(3):e70122. doi: 10.1002/prp2.70122.

ABSTRACT

Cardiovascular diseases are the leading cause of mortality worldwide, with dyslipidemia as a major modifiable risk factor. This study aimed to assess 25-year trends in lipid-lowering agent consumption in Croatia from 2000 to 2023. We conducted a population-based analysis using IMS and IQVIA databases, calculating drug utilization in defined daily doses per 1000 inhabitants per day (DDD/1000) and evaluating financial expenditures and prescribing patterns. Over the study period, total lipid-lowering drug consumption increased more than 30-fold, from 4.91 DDD/1000 in 2000 to 152.56 DDD/1000 in 2023. Statins, particularly atorvastatin and rosuvastatin, drove this trend, while the uptake of PCSK9 inhibitors and ezetimibe reflected an evolving therapeutic landscape. Financial expenditures peaked in 2010, declined until 2015, and rose again by 2023, with average drug prices per DDD decreasing significantly. The observed increase in lipid-lowering therapy correlated with enhanced adherence to international guidelines and expanded patient access. However, administrative barriers and restrictive reimbursement policies continue to limit optimal utilization of newer agents. These findings underscore the importance of evidence-based policy development to address clinical inertia and improve cardiovascular outcomes in Croatia.

PMID:40384513 | DOI:10.1002/prp2.70122