Nevin Manimala

Biometrics. 2025 Jan 7;81(1):ujaf015. doi: 10.1093/biomtc/ujaf015.

ABSTRACT

Researchers commonly use difference-in-differences (DiD) designs to evaluate public policy interventions. While methods exist for estimating effects in the context of binary interventions, policies often result in varied exposures across regions implementing the policy. Yet, existing approaches for incorporating continuous exposures face substantial limitations in addressing confounding variables associated with intervention status, exposure levels, and outcome trends. These limitations significantly constrain policymakers’ ability to fully comprehend policy impacts and design future interventions. In this work, we propose new estimators for causal effect curves within the DiD framework, accounting for multiple sources of confounding. Our approach accommodates misspecification of a subset of intervention, exposure, and outcome models while avoiding any parametric assumptions on the effect curve. We present the statistical properties of the proposed methods and illustrate their application through simulations and a study investigating the heterogeneous effects of a nutritional excise tax under different levels of accessibility to cross-border shopping.

PMID:39989323 | DOI:10.1093/biomtc/ujaf015

Biometrics. 2025 Jan 7;81(1):ujaf016. doi: 10.1093/biomtc/ujaf016.

ABSTRACT

Studies have shown that the effect an exposure may have on a disease can vary for different subtypes of the same disease. However, existing approaches to estimate and compare these effects largely overlook causality. In this paper, we study the effect smoking may have on having colorectal cancer subtypes defined by a trait known as microsatellite instability (MSI). We use principal stratification to propose an alternative causal estimand, the Subtype-Free Average Causal Effect (SF-ACE). The SF-ACE is the causal effect of the exposure among those who would be free from other disease subtypes under any exposure level. We study non-parametric identification of the SF-ACE and discuss different monotonicity assumptions, which are more nuanced than in the standard setting. As is often the case with principal stratum effects, the assumptions underlying the identification of the SF-ACE from the data are untestable and can be too strong. Therefore, we also develop sensitivity analysis methods that relax these assumptions. We present 3 different estimators, including a doubly robust estimator, for the SF-ACE. We implement our methodology for data from 2 large cohorts to study the heterogeneity in the causal effect of smoking on colorectal cancer with respect to MSI subtypes.

PMID:39989322 | DOI:10.1093/biomtc/ujaf016

Biometrics. 2025 Jan 7;81(1):ujaf012. doi: 10.1093/biomtc/ujaf012.

ABSTRACT

Dose-finding trials are a key component of the drug development process and rely on a statistical design to help inform dosing decisions. Triallists wishing to choose a design require knowledge of operating characteristics of competing methods. This is often assessed using a large-scale simulation study with multiple designs and configurations investigated, which can be time-consuming and therefore limits the scope of the simulation. We introduce a new approach to the design of simulation studies of dose-finding trials. The approach simulates all potential outcomes that individuals could experience at each dose level in the trial. Datasets are simulated in advance and then applied to each of the competing methods to enable a more efficient head-to-head comparison. Furthermore, individual trial datasets can be interrogated to understand when designs deviate in their decision making. In three case-studies, we show sizeable reductions in Monte Carlo error for comparing a performance metric between two competing designs. Efficiency gains depend on the similarity of the designs. Comparing two Phase I/II design variants, with high correlation of recommending the same optimal biologic dose, we show that the new approach requires a simulation study that is approximately 48 times smaller than the conventional approach. Furthermore, advance-simulated trial datasets can be reused to assess the performance of designs across multiple configurations. We recommend researchers consider this more efficient simulation approach in their dose-finding studies and we have updated the R package escalation to help facilitate implementation.

PMID:39989321 | DOI:10.1093/biomtc/ujaf012

J Laparoendosc Adv Surg Tech A. 2025 Feb 24. doi: 10.1089/lap.2024.0273. Online ahead of print.

ABSTRACT

Background: Incisional hernias (IHs) represent a frequently encountered postoperative complication in patients undergoing liver transplantation. Traditionally, these hernias have been addressed through open surgical techniques. However, laparoscopic repair has been increasingly recognized for its association with a reduced complication rate in the management of ventral hernias. Our objective is to conduct a comparative analysis of the outcomes associated with open versus laparoscopic repair techniques in liver transplant recipients. Methods: We conducted a comprehensive literature review across multiple databases, including PubMed, Cochrane, LILACS, SciELO, and EMBASE, to identify studies that compare the efficacy of open and laparoscopic repair methods for IHs postliver transplantation. For the statistical analysis of gathered data, we used the Review Manager software, version 5.4. To evaluate the variability among the study outcomes, we assessed heterogeneity using the I² statistic. Results: After an initial screening of 334 studies, 6 studies with a combined total of 338 patients fulfilled our inclusion criteria. Our analysis revealed that laparoscopic repair tends to be associated with longer operation times, with a mean difference of 20.30 minutes (confidence interval [CI]: 2.14-38.46; P = .03). We observed no significant differences between laparoscopic and open repair regarding infection rates, recurrence rates, overall surgical complications, or hospital stay duration. Conclusion: Both surgical approaches yield comparable postoperative outcomes. However, laparoscopic repair is associated with an increased operation time duration. To substantiate these findings, further research involving prospective, randomized studies is necessary.

PMID:39989303 | DOI:10.1089/lap.2024.0273

Int J Rheum Dis. 2025 Feb;28(2):e70138. doi: 10.1111/1756-185X.70138.

ABSTRACT

AIM: Rheumatoid arthritis (RA) is an autoimmune disease that is marked by inflammatory response. PNPLA2 (phospholipase patatin-like) which encodes ATGL (adipose triglyceride lipase) also been identified as playing in inflammation. G0S2 (G0/G1) switch gene has been identified as one of the selective inhibitors of ATGL. PNPLA2 and G0S2 may be factors that can help predict the relationship between molecules affecting inflammation, as well as identify inflammatory pathways through genes involved in the metabolic pathway.

METHODS: In the present study, we analyzed the expression levels of PNPLA2 and G0S2 genes as well as their protein concentrations by real-time PCR and immunoassay, respectively on 60 peripheral blood mononuclear cells (PBMC) which are included into 3 different groups of new case patients with RA, chronic patients with RA, and the control individuals. Also, to obtain more accurate information and results, the synovial fluid, triglyceride, cholesterol, and ESR levels were also analyzed. Statistical analysis was then performed with the software SPSS-18.

RESULTS: PNPLA2 gene expression level was significantly increased in the newly diagnosed patients and the chronic RA patients in compared to the control group. Also, the serum levels of ATGL in the newly diagnosed patients and the chronic RA patients were significantly reduced compared to the control group. The gene and protein levels of G0S2 in the newly diagnosed patients elevated compared to other groups, but interestingly this increase in PBMCs was not significant.

CONCLUSIONS: This is predicted that PNPLA2 gene expression in PBMCs is not only regulated by G0S2 gene, but different regulatory factors can also affect the expression level of this gene in the immune cells.

PMID:39989302 | DOI:10.1111/1756-185X.70138

Diabetes Technol Ther. 2025 Feb 24. doi: 10.1089/dia.2025.0033. Online ahead of print.

ABSTRACT

Background: In a prior work, a virtual continuous glucose monitoring (CGM) trace was generated for each of the 1441 participants in the landmark Diabetes Control and Complications trial (DCCT). These new data allow us to compare whether time-in-tight-range (TITR) is a better predictor of diabetic microvascular complications (specifically retinopathy development or progression) than time-in-range (TIR). Methods: Discrete Cox proportional hazard models were used to calculate the hazard ratios (HRs) for the development/progression of retinopathy. Results: For a 1.0 standard deviation (SD) change, the adjusted HR (95% confidence interval) was 2.67 (2.33-3.06) for TIR, 2.74 (2.36-3.18) for TITR, and 2.37 (2.13-2.65) for HbA1c; a similar pattern of results was obtained for a 0.5 SD change. Computing Harrell’s C-statistic showed that a survival model adjusted for TIR, TITR, or HbA1c had similar predictive performance. Conclusion: The associations of TIR and TITR with retinopathy development or progression were similar to HbA1c in the virtual DCCT CGM dataset.

PMID:39989301 | DOI:10.1089/dia.2025.0033

Nurs Crit Care. 2025 Mar;30(2):e13278. doi: 10.1111/nicc.13278.

ABSTRACT

BACKGROUND: Early mobilization is one proposed strategy for reducing complications and optimizing patient outcomes. Nurses play an essential role in patient monitoring and co-ordination.

AIMS: To assess the effects of a nurse-involved early mobilization programme on muscle strength and intensive care unit (ICU) length of stay and identify the components of an early mobilization programme.

STUDY DESIGN: A systematic review and meta-analysis were conducted. MEDLINE (PubMed), Embase, Cochrane and CINAHL databases were searched. Eligible studies included randomized controlled trials (RCTs) and non-randomized studies of adult ICU patients undergoing early mobilization. The studies were appraised using RoB 2.0 and ROBINS-I tools, and a meta-analysis was performed using Rstudio 2023.06.2.

RESULTS: Nine studies were selected from 943 studies. Four studies involved only ICU nurses, while five involved multidisciplinary teams. Concerns about bias were raised in four RCTs, and two non-randomized studies had moderate bias risk. Interventions involved progressive exercise steps, but none detailed the specific role of nurses. Early mobilization significantly decreased ICU length of stay (95% CI: -3.22, -0.11; p = .04), although it did not improve muscle strength (95% CI: -0.86, 0.99; p = .80).

CONCLUSIONS: Nurse-involved early mobilization was associated with a reduction in ICU stay, although it did not impact muscle strength. The nurses’ roles were not specifically defined.

RELEVANCE TO CLINICAL PRACTICE: An analysis of relevant tasks is necessary to clarify the role of nurses in early mobilization and to provide optimal care. Including these roles is crucial in the development of standardized early mobilization.

PMID:39989266 | DOI:10.1111/nicc.13278

Med Decis Making. 2025 Feb 24:272989X251319794. doi: 10.1177/0272989X251319794. Online ahead of print.

ABSTRACT

BACKGROUND: We aimed to illustrate that health economists should consider individual heterogeneity when solving the problem of finding the optimal combination of sensitivity and specificity that maximizes the average health utility of a target population in a screening program.

METHODS: A theoretical framework compares the solution under standard economics of diagnoses to the optimal combination under an endogenous uptake analysis, where screening participation is given by heterogenous health preferences. An applied example used calibrated parameters with real data from the bowel cancer screening program in the United Kingdom. Scenario analyses show how the results would change with parameter values, if disease risk and health utilities were not independent and if screening uptake were not completely determined by health preferences.

RESULTS: A general theoretical result states that the endogenous uptake analysis leads to a weakly higher true- and false-positive rate than would be optimal under the standard approach. In the same way, the endogenous solution would lead to a lower uptake rate. The base-case scenario of the applied example illustrates that a screening program using the endogenous solution would generate 21.1% more quality-adjusted life-years than when using the standard solution. The scenario analyses show when the endogenous analysis is most valued and that the general result applies for a wide range of situations when theoretical assumptions are relaxed.

LIMITATIONS: The results obtained are valid under the assumptions made. Analysts should evaluate if those could hold in the applied screening context.

CONCLUSIONS: Individual heterogeneity and uptake decisions are relevant factors to consider in the problem of finding an optimal combination of sensitivity and specificity for a screening test.

HIGHLIGHTS: The value of screening programs can be higher if heterogeneity of preferences in the target population is considered.The optimal operation of a screening test depends on health utilities of the target population and on the heterogeneity of these health utilities.Under heterogeneity of health utilities, the optimal operation of a screening test does not maximize screening uptake.A general theoretical result states that the endogenous uptake analysis leads to a weakly higher true- and false-positive rate than would be optimal under a standard approach; this is true for a wide range of situations.

PMID:39989263 | DOI:10.1177/0272989X251319794

Technol Cancer Res Treat. 2025 Jan-Dec;24:15330338251323314. doi: 10.1177/15330338251323314.

ABSTRACT

Introduction: Exosomes play significant roles in transferring cargo materials like proteins, RNAs (including miRNAs), and DNA. However, the role of serum exosome shuttled RNAs and miRNAs in head and neck cancer (HNC) remains unclear. This study assessed the diagnostic and prognostic significance of exosomal miR-17, miR-20a, and TGFBR2 in HNC patients. Methods: Exosomes were isolated, from 400 confirmed HNC patients and 400 healthy controls, and characterized by NTA, TEM, Immunolabelling, and ELISA. Quantitative PCR was used to check the expressions of exosomal molecules. Oxidative stress was also measured through ELISA in cancer patients and healthy controls. Results: Data analysis revealed significant dysregulation in the expressional levels of miR-17 (p < .0001), miR-20a (p = .0003), and TGFBR2 (p = .0005), which were found associated with aggressiveness and poor survival of HNC patients. Spearman correlation revealed a positive statistically significant association between miR-20a versus miR-17 (r = 0.534; p < .01), while a negative correlation was found between TGFBR2 versus miR-17 (r = -0.240; p = .015). Significantly decreased levels of peroxidase (POD) (p < .0001) and an increased level of 8-Oxoguanine (p < .0001) were observed. Conclusion: The results showed that these exosomal miRNAs and target gene may serve as potential and noninvasive diagnostic and prognostic markers for head and neck cancer patients.

PMID:39989256 | DOI:10.1177/15330338251323314

Int J Low Extrem Wounds. 2025 Feb 24:15347346251321524. doi: 10.1177/15347346251321524. Online ahead of print.

ABSTRACT

BACKGROUND: Multiple studies have shown metabolites may have potential effects on Charcot foot. However, the Mendelian randomization method has not yet explored the relationship between metabolites and Charcot foot.

METHODS: We selected genetic variants from the publicly available Genome-wide Association Studies (GWAS) summary database to represent 1400 metabolites described in recent research. Mendelian randomization (MR) analysis was carried out to examine the relationships between these metabolites and Charcot foot. Significant single nucleotide polymorphism (SNP) data associated with exposure were screened out through association analysis. Valid instrumental variables (IVs) were then selected, excluding SNPs with F-statistic values below 10. The MR analyses primarily employed the inverse variance weighted (IVW) method. Bayesian weighted Mendelian randomization (BWMR), constrained maximum likelihood(cML), contamination mixture(Conmix), robust adjusted profile score(RAPS), and debiased inverse-variance weighted(deIVW) method were used to enhance the results. Colocalization analysis was performed to identify shared causal genetic variants associated with the resulting phenotypes. Sensitivity analyses, including assessments of Cochrane’s Q test, egger intercept, and MR PRESSO test were conducted to confirm the robustness of the results.

RESULTS: After preliminary MR exploration, the IVW results exhibited positive causal relationships between hexadecenedioate (C16:1-DC) levels (OR = 0.698, 95%CI: 0.586 to 0.831, P_FDR = 0.040), octadecadienedioate (C18:2-DC) levels (OR = 0.665, 95%CI: 0.552 to 0.800, P_FDR = 0.021), octadecanedioylcarnitine (C18-DC) levels (OR = 0.676, 95%CI: 0.553 to 0.827, P_FDR = 0.067) and Charcot foot. Colocalization analysis indicated that the above three metabolites share a common causal variant at the same genomic location with Charcot foot. Sixty-four metabolites with suggestive causal relationships with Charcot foot were also identified, among which 25 kinds of metabolites were positively correlated with Charcot foot, and 33 metabolites were negatively associated with Charcot foot. The BWMR, cML, Conmix, RAPS, and deIVW results supported our preliminary MR results. In several results, sensitivity analyses showed heterogeneity and horizontal pleiotropy, while the causal relationships obtained through FDR correction did not show any significant heterogeneity and horizontal pleiotropy. No reverse causal association was detected.

CONCLUSION: We detected protective and risk metabolites in Charcot foot. Controlling metabolites may decrease Charcot foot risk and serve as a novel therapeutic biomarker for the therapy.

PMID:39989250 | DOI:10.1177/15347346251321524