Firth Logistic Regression Research Articles

Systematic identification of pathogenic variants of non-small cell lung cancer in the promoters of DNA-damage repair genes

Deficiency in DNA-damage repair (DDR) genes, often due to disruptive coding variants, is linked to higher cancer risk. Our previous study has revealed the association between rare loss-of-function variants in DDR genes and the risk of lung cancer. However, it is still challenging to study the predisposing role of rare regulatory variants of these genes. Based on whole-genome sequencing data from 2984 patients with non-small cell lung cancer (NSCLC) and 3020 controls, we performed massively parallel reporter assays on 1818 rare variants located in the promoters of DDR genes. Pathway- or gene-level burden analyses were performed using Firth's logistic regression or generalized linear model. We identified 750 rare functional regulatory variants (frVars) that showed allelic differences in transcriptional activity within the promoter regions of DDR genes. Interestingly, the burden of frVars was significantly elevated in cases (odds ratio [OR]=1.17, p=0.026), whereas the burden of variants prioritized solely based on bioinformatics annotation was comparable between cases and controls (OR=1.04, p=0.549). Among the frVars, 297 were down-regulated transcriptional activity (dr-frVars) and 453 were up-regulated transcriptional activity (ur-frVars); especially, dr-frVars (OR=1.30, p=0.008) rather than ur-frVars (OR=1.06, p=0.495) were significantly associated with risk of NSCLC. Individuals with NSCLC carried more dr-frVars from Fanconi anemia, homologous recombination, and nucleotide excision repair pathways. In addition, we identified seven genes (i.e., BRCA2, GTF2H1, DDB2, BLM, ALKBH2, APEX1, and RAD51B) with promoter dr-frVars that were associated with lung cancer susceptibility. Our findings indicate that functional promoter variants in DDR genes, in addition to protein-truncating variants, can be pathogenic and contribute to lung cancer susceptibility. National Natural Science Foundation of China, Youth Foundation of Jiangsu Province, Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer of Chinese Academy of Medical Sciences, and Natural Science Foundation of Jiangsu Province.

Sociodemographic and maternal health-related factors associated with mortality among children under three in Bangladesh: an analysis of data from Bangladesh Demographic and Health Survey 2017-18

BackgroundChild mortality remains remarkably high in many low- and middle-income countries (LMICs), including Bangladesh. This study aimed to identify the sociodemographic and maternal health-related factors associated with under three (U3) child mortality in Bangladesh.MethodsWe extracted data of 5299 U3 children from Bangladesh Demographic and Health Survey (BDHS) 2017-18. We used descriptive statistics to summarize the data. The chi-square (χ2) test, simple and multiple Firth logistic regression were performed to test the associations between priori-defined factors and U3 mortality.ResultsIn Bangladesh, the U3 child mortality rate was 35 deaths per 1,000 live births, with a median age at death of less than one month. The adjusted model revealed that the odds of U3 child mortality were higher among children born to mothers aged between 30 and 39 years [adjusted odds ratio (AOR) = 2.01, 95% confidence interval (CI): 1.30–3.11; p-value (p) = 0.002], those who did not use any contraceptive [AOR = 2.57, 95% CI: 1.90–3.47; p < 0.001], with first pregnancy [AOR = 14.91, CI: 4.60–48.30; p < 0.001], had birth interval less than 24 months [AOR = 2.10, CI: 1.23–3.60; p = 0.007], children born to mothers who delivered vaginally [AOR = 3.18, 95% CI: 2.07–4.87; p < 0.001]. However, lower odds of mortality were observed among children of mothers with higher education levels [AOR = 0.50, 95% CI: 0.28–0.90; p = 0.021] and families with more than five members [AOR = 0.61, 95% CI: 0.45–0.83; p < 0.01]. In addition, religion, birth attendant during delivery, and the child’s birth order were significantly associated with U3 child mortality, whereas mortality did not vary significantly across the divisions.ConclusionsHigher odds of U3 child mortality were associated with mothers who did not use contraceptives, delivered vaginally, and were aged 30–39 years in Bangladesh. Conversely, higher maternal education and larger family size were associated with lower odds of U3 child mortality. The findings suggest that community-based family planning awareness programs focused on contraceptive use, as it prevents childbirth and is also a marker of health service usage.

Predictive factors for early mortality after EUS-guided gastroenterostomy in malignant gastric outlet obstruction

Background and study aim: Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) has recently emerged as a potential treatment option for malignant gastric outlet obstruction (mGOO), with a relatively long duration of patency and low rate of reintervention. Its intrinsic risk for serious adverse events and high procedure cost mandates careful patient selection beyond the common safety profiles. This study aimed to assess for predictors of early post-EUS-GE mortality. Patients and methods: We conducted a retrospective analysis of all patients with unresectable mGOO who underwent EUS-GE. Predictive factors for postoperative 30-day mortality with crude and adjusted hazard ratios were examined using univariate and multivariate penalized likelihood Firth logistic regression analyses. Results: Technical and clinical success was achieved in 96.7% and 93.1% of the patients, respectively. The 30-day mortality rate after the procedure was 11.7%, and no procedural complications were observed. The 30-day mortality group had a significantly low rate of initial clinical success (66.7% vs. 96.2%, p=0.007). Univariate analysis identified significantly higher postoperative 30-day mortality in patients with poor baseline ECOG performance status scale (≥2) and ascites. The presence of grade 2 ascites was confirmed as an independent predictive factor in the multivariate analysis (adjusted hazard ratio 52.41, 95% confidence interval 1.55 to 1775.64, p=0.024). Conclusion: EUS-GE should be carefully considered for patients with ascites which was an independent predictor for early mortality after procedure in mGOO, especially those with grade 2 or higher level of ascites.

A goodness-of-fit measure for logistic regression under separation

Logistic regression models have a severe problem called separation. The maximum likelihood estimator does not exist in logistic regression models for data structures under separation. Under separation, the forcibly estimated maximum likelihood estimate may have an extremely large value. Separation often occurs when the size of dataset is small. Consequently, goodness-of-fit measures based on the likelihood ratio and those based on covariance functions using the maximum likelihood estimate indicate that the model is excessively good regardless of the cause of the separation. The Firth and exact logistic regression methods are valid estimation methods for separation problems. Therefore, we propose methods to reasonably evaluate the goodness-of-fit measures of statistical models under separation with dataset of a small sample size with the abovementioned methods. The goodness-of-fit measures based on covariance functions which are a generalization of the multiple correlation coefficient, referred to as the regression correlation coefficient and the entropy coefficient of determination are then used combined with the abovementioned methods for the separation data. In addition, we conducted a data analysis using the definition of the non separation ratio based on the regression depth.

Prevalence and predictors of right ventricular dysfunction among adults living with HIV in northwest Nigeria.

People living with the human immunodeficiency virus (PLWH) are at increased risk of cardiovascular diseases. Right ventricular (RV) function has important prognostic value in cardiac pathology, and advances in imaging modalities, such as transthoracic echocardiography have enabled in-depth RV studies. There is, however, a scarcity of multiparameter RV function studies in PLWH in low- and middle-income settings, such as Nigeria. The aim of this study is to determine the prevalence and predictors of RV dysfunction among adult PLWH in northwest Nigeria. This is a retrospective cross-sectional study conducted between February 1, 2023 and August 31, 2023. We consecutively recruited 330 adults [median age 45 years, interquartile range (IQR), 38 to 52 years, 61% female] attending human immunodeficiency virus (HIV) and general outpatient clinics in a tertiary hospital in northwest Nigeria. They included 110 antiretroviral therapy (ART)-experienced PLWH, 110 ART-naïve PLWH, and 110 age- and sex-matched HIV-negative control subjects. All participants had conventional two-dimensional (2D), tissue Doppler (TDI), and speckle tracking (2D-STE) echocardiography to estimate left ventricular (LV) and RV systolic and diastolic function, peak systolic and diastolic myocardial velocities, RV and LV longitudinal strain, and chamber dimensions. All participants also underwent 12-lead electrocardiography. Multiple linear and Firth's logistic regression modeling were performed to assess for independent predictors of RV myocardial performance index (RVMPI) as a continuous and as a dichotomous variable, respectively. The prevalence of RV dysfunction, as determined by the RVMPI among HIV-positive participants was 14.5% [95% confidence interval (CI): 10.5-19.8%] compared to 0% (95% CI: 0.0-3.4%) for those without HIV. Among participants with HIV, RVMPI was associated with participant age (P<0.001) and left ventricular ejection fraction (LVEF) (P<0.001). Results were similar when RVMPI was dichotomized. The association between RV dysfunction and LVEF was modified by ART status: a 10% decrease in LVEF was associated with an average decrease of 0.08 in RVMPI among participants who were ART-experienced (β=-0.08, P<0.001) but a lesser decrease among those who were ART- naïve (β=-0.03, P=0.14). This study highlights the complexity of RV dysfunction in PLWH and underscores the importance of LVEF and age as key factors influencing the risk of RV dysfunction in PLWH.

Food Insecurity Status and Health Care Utilization Among COPD Patients: A Retrospective Study.

Government programs-targeting chronic disease patients with high health care costs-focus on clinical conditions, factors internal to the health care system, and individual patient education, not on addressing modifiable social determinants of health to reduce health care utilization. To evaluate differences in sociodemographic variables and health care utilization between patients with chronic obstructive pulmonary disease (COPD) who reported food insecurity and those who did not. This descriptive retrospective cross-sectional study used data from the electronic health records of a convenience sample of 854 participants with a discharge diagnosis of COPD or COPD with acute exacerbation, admitted via the emergency department of participating hospitals in Southern California. Chi-square (or Fisher's exact) tests and t tests were used to evaluate group differences, and multivariate (or Firth) logistic regression to identify factors that increased the odds of emergency department visits and hospitalizations. Significant differences between groups were identified for food insecurity (sometimes or often vs never insecure) and age (P < .001), race (P = .022), medical insurance (P < .001), zip code (P = .022), homeless status (P < .001), smoking status (P < .001), and emergency department visits (P = .033). No significant differences were found for food insecurity and hospitalizations (P = .592). This study contributes to the growing body of research supporting the association of upstream social factors (food insecurity, homelessness, zip code) and downstream health outcomes (repeated emergency room visits), and how existing programs can be effectively utilized to impact downstream health outcomes such as health care utilization.

Impact of the COVID-19 Pandemic on Group A Streptococcal Necrotizing Soft Tissue Infections: A Retrospective Cohort Study.

Necrotizing soft tissue infections (NSTIs) are often caused by group A Streptococcus (GAS). As the number of invasive GAS infections decreased during the coronavirus disease 2019 (COVID-19) pandemic restrictions, this study aimed to compare the occurrence of GAS-NSTIs before, during, and after the COVID-19 pandemic restrictions. This retrospective cohort study included adult patients with NSTIs admitted to the intensive care unit (ICU) of the University Hospital Zurich, Switzerland, from July 2008 to December 2023. NSTI cases were categorized as pre-, during, and postrestrictions. The primary outcome was the proportion of GAS in NSTI, and the exploratory secondary outcome was in-hospital death. A data analysis was conducted using Firth logistic regression adjusted for age, sex, diabetes, and initially affected body region. Overall, 74 NSTI cases were identified, with 49 occurring before, 8 during, and 17 after the pandemic restrictions. GAS was isolated in 27 (36%) cases, with 17 (35%) pre- and 10 (59%) postrestrictions, but none during the restrictions. NSTIs caused by other bacteria persisted during the restrictions. The odds of GAS were significantly lower during the restrictions (adjusted odds ratio, 0.02; 95% CI, 0.001-0.81) compared with after, while no significant differences were found between the pre- and postrestriction periods. The significant decrease of GAS-NSTIs during the COVID-19 pandemic restrictions suggests that isolation measures may have prevented the transmission of GAS, resulting in a decline of GAS-NSTIs while NSTIs caused by bacteria transmitted by alternative routes persisted.

Unplanned hospital admissions within 24 h after 53,185 surgical procedures at a U.S. ambulatory surgery center

BackgroundUnplanned admission after surgery at an ambulatory surgery center (ASC) is an established measure of the quality of care and can affect the patient’s experience. Previous studies on this topic are generally dated, focused on a single specialty, or studied 30-day admissions after ambulatory surgery. Few studies have reported admission within 24 h after surgery at an ASC which is a different but important measure of the quality of anesthetic and surgical care. Understanding admissions within 24 h of surgery can identify opportunities for improvement immediately after surgery. Therefore, our study was designed to assess the incidence and risk factors for unplanned hospital admissions within 24 h after surgery performed at a hospital ASC.MethodsAfter Institutional Review Board approval, a retrospective analysis was performed on all adult patients who underwent surgery at a US ASC between January 1, 2016, and December 31, 2022. Data were obtained from the hospital’s electronic medical record. The study sample was divided into two groups: those with an unplanned hospital admission within 24 h after surgery and those without an unplanned hospital admission. To evaluate risk factors for unplanned hospital admissions, univariate analyses with p value < 0.05 were utilized to identify significant patient variables related to hospital admissions. These variables were further adjusted using a multivariable Firth logistic regression. Descriptive statistics were used to explore the number of patients in different variable categories.ResultsOverall, 53,185 cases were identified for the 7-year period. The incidence of unplanned hospital admission over this period was 0.09% (95% CI 0.07–0.1122%; ranging from 0.05 to 0.12% per year. In the multivariable model, surgery duration (OR 1.010, 95% CI 1.007–1.012, p value < 0.0001), peripheral vascular disease (OR 14.489, 95% CI 4.862–43.174, p value < 0.0001), and deep venous thrombosis (OR 5.527, 95% CI 1.909–16.001, p value = 0.0016) were significantly associated with unplanned hospital admission.ConclusionThe overall incidence of unplanned hospital admission after surgery at a large tertiary care ambulatory surgery center is very low. This admission rate can also serve as a reference point for future studies and quality improvement initiatives.

Tutorial on Firth's Logistic Regression Models for Biomarkers in Preclinical Space.

Preclinical studies are broad and can encompass cellular research, animal trials, and small human trials. Preclinical studies tend to be exploratory and have smaller datasets that often consist of biomarker data. Logistic regression is typically the model of choice for modeling a binary outcome with explanatory variables such as genetic, imaging, and clinical data. Small preclinical studies can have challenging data that may include a complete separation or quasi-complete separation issue that will result in logistic regression inflated coefficient estimates and standard errors. Penalized regression approaches such as Firth's logistic regression are a solution to reduce the bias in the estimates. In this tutorial, a number of examples with separation (complete or quasi-complete) are illustrated and the results from both logistic regression and Firth's logistic regression are compared to demonstrate the inflated estimates from the standard logistic regression model and bias-reduction of the estimates from the penalized Firth's approach. R code and datasets are provided in the supplement.

Prevalence of Strongyloides stercoralis and other helminths in four districts of Madagascar

BackgroundEstimation of prevalence of Strongyloides stercoralis infection is required in endemic areas, in order to identify areas in need of control programmes. Data on prevalence of strongyloidiasis in Madagascar are scant. Aim of this work was to estimate prevalence of S. stercoralis in four districts of Madagascar.MethodsFecal and serum samples collected in the context of a previous study on schistosomiasis were tested with S. stercoralis real-time PCR and serology, respectively. A multiplex real-time PCR for Ascaris lumbricoides, Ancylostoma duodenalis, Necator americanus, and Trichuris trichiura was done on fecal samples collected in the areas demonstrating higher prevalence of strongyloidiasis. Comparisons between proportions were made using Fisher exact test, with false discovery rate correction used for post-hoc comparisons. A multivariable Firth logistic regression model was used to assess potential risk factors for S. stercoralis infection.ResultsOverall, 1775 serum samples were tested, of which 102 of 487 (20.9%) and 104 of 296 (35.2%) were serological-positive in Marovoay and in Vatomandry districts (both coastal areas), respectively, compared to 28 of 496 (5.6%) and 30 of 496 (6.1%) in Tsiroanomandidy and in Ambositra districts (both highlands), respectively (adj. p < 0.001). PCR for S. stercoralis was positive in 15 of 210 (7.1%) and in 11 of 296 (3.7%) samples from Marovoay from Vatomandry, respectively, while was negative for all samples tested in the other two districts. High prevalence of A. lumbricoides (45.9%), hookworm (44.6%) and T. trichiura (32.1%) was found in Vatomandry. In the multivariable analysis, strongyloidiasis was associated with hookworm infection. Hookworm infection was also associated with male sex and lower education level.ConclusionsS. stercoralis prevalence proved higher in coastal areas compared to highlands. Different climatic conditions may explain this distribution, along with previous rounds of anthelminthics distributed in the country, which may have reduced the parasite load in the population. The high prevalence of the other soil-transmitted helminths (STH) in Vatomandry was unexpected, given the good coverage with benzimidazole in control campaigns. Further studies are needed to explore the risk factors for STH and S. stercoralis infections in Madagascar, in order to align with the WHO recommendations.

Immunogenicity and Predictive Factors Associated with Poor Response after Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Lung Transplant Patients.

Lung transplant patients are more likely to develop severe coronavirus disease 2019 (COVID-19) compared with the general population and should be vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, previous studies have reported reduced vaccination immunogenicity in lung transplantation patients. We aimed to investigate the serological response and associated factors after SARS-CoV-2 vaccination in this population. Lung transplant patients without a history of contracting coronavirus disease who had received a second or higher dose of SARS-CoV-2 vaccination were enrolled. The anti-SARS-Cov-2 spike and neutralizing antibody levels were measured in blood samples. Firth's logistic regression analysis was performed to assess the factors associated with non-response after vaccination. Forty-six lung transplant patients were enrolled, of which sixteen (34.8%) showed a serological response to vaccination. All patients who received anti-SARS-CoV-2 vaccination before transplantation (n = 5) exhibited a serological response. No significant difference was observed in anti-SARS-CoV-2 S antibody or neutralization titers based on the number and timing of vaccination. Firth's logistic regression showed an association between lower hemoglobin levels (odds ratio, 0.59; confidence interval, 0.35-0.92; p = 0.017) and non-response to SARS-CoV-2 vaccination. Lung transplant patients showed poor serologic responses after SARS-CoV-2 vaccination in this pilot study; anemia may be associated with this poor response.

The association between governance mechanisms and engagement in commercialisation and entrepreneurship of Romanian public research institutes

This study investigates the connection between the governance structure of a public research institute (PRI) and its inclination towards entrepreneurship and patenting, in the form of spin-offs and granted patents, in Romania, an emerging economy. Employing a combination of negative binomial and Firth logistic regressions, the research examines the links between the composition of the board of directors (BD) and PRI's knowledge and technology transfer (KTT) and entrepreneurial efforts over a period of eleven years (2012–2022). The results show that gender diversity in the BD does not impact the establishment of new firms and patenting. Moreover, the likelihood of spin-off creation in female-led PRIs is lower than in male-led ones, while the general director's gender has minimal impact on the patenting process. On the other hand, BD diversity in terms of external directors, namely the industry representatives, strongly influences the entrepreneurial orientation of the PRI. The same connection is shown with the existence of technology transfer offices. Scientific excellence is slightly complementary with patenting. Finally, geographic location has a weak mixed effect on the creation of spin-offs and patenting. Our paper contributes to the industrial organisational literature, which has not paid enough attention to the role of research institutes in science commercialisation, especially in emerging economies.

Reparametrized Firth's Logistic Regressions for Dose-Finding Study With the Biased-Coin Design.

Finding an adequate dose of the drug by revealing the dose-response relationship is very crucial and a challenging problem in the clinical development. The main concerns in dose-finding study are to identify a minimum effective dose (MED) in anesthesia studies and maximum tolerated dose (MTD) in oncology clinical trials. For the estimation of MED and MTD, we propose two modifications of Firth's logistic regression using reparametrization, called reparametrized Firth's logistic regression (rFLR) and ridge-penalized reparametrized Firth's logistic regression (RrFLR). The proposed methods are designed by directly reducing the small-sample bias of the maximum likelihood estimate for the parameter of interest. In addition, we develop a method on how to construct confidence intervals for rFLR and RrFLR using profile penalized likelihood. In the up-and-down biased-coin design, numerical studies confirm the superior performance of the proposed methods in terms of the mean squared error, bias, and coverage accuracy of confidence intervals.

Relationships between quantitative magnetic resonance imaging measures at the time of return to sport and clinical outcomes following acute hamstring strain injury

Hamstring strain injuries (HSI) are a common occurrence in athletics and complicated by high rates of reinjury. Evidence of remaining injury observed on magnetic resonance imaging (MRI) at the time of return to sport (RTS) may be associated with strength deficits and prognostic for reinjury, however, conventional imaging has failed to establish a relationship. Quantitative measure of muscle microstructure using diffusion tensor imaging (DTI) may hold potential for assessing a possible association between injury-related structural changes and clinical outcomes. The purpose of this study was to determine the association of RTS MRI-based quantitative measures, such as edema volume, muscle volume, and DTI metrics, with clinical outcomes (i.e., strength and reinjury) following HSI. Spearman’s correlations and Firth logistic regressions were used to determine relationships in between-limb imaging measures and between-limb eccentric strength and reinjury status, respectively. Twenty injuries were observed, with four reinjuries. At the time of RTS, between-limb differences in eccentric hamstring strength were significantly associated with principal effective diffusivity eigenvalue λ1 (r = -0.64, p = 0.003) and marginally associated with mean diffusivity (r = -0.46, p = 0.056). Significant relationships between other MRI-based measures of morphology and eccentric strength were not detected, as well as between any MRI-based measure and reinjury status. In conclusion, this preliminary evidence indicates DTI may track differences in hamstring muscle microstructure, not captured by conventional imaging at the whole muscle level, that relate to eccentric strength.

Exploring the Linkages between farm efficiency, farm environmental performance, and agri-environmental scheme adoption: Lessons from France

The agricultural detrimental effects on the environment are a source of concern. Public mea-sures, such as agri-environmental schemes (AES), have been designed to incentivize farmers to adopt more sound environmental practices on the farm. In this study, we examine the effects of past initial economic and environmental performances on AES adoption by focusing on crop farms. Using Firth's logistic regression to address small sample bias with French FADN data from 1997 to 2007, we mainly find that technical efficiency has heterogeneous effects on AES adoption, depending on environmental indexes. This result suggests the presence of windfall effects. We also show complex interactions (antagonism or synergy) between economic and environmental performances in adoption decisions, and heterogeneous effects depending on the type of farming.The agricultural detrimental effects on the environment are a source of concern. Public mea-sures, such as agri-environmental schemes (AES), have been designed to incentivize farmers to adopt more sound environmental practices on the farm. In this study, we examine the effects of past initial economic and environmental performances on AES adoption by focusing on crop farms. Using Firth's logistic regression to address small sample bias with French FADN data from 1997 to 2007, we mainly find that technical efficiency has heterogeneous effects on AES adoption, depending on environmental indexes. This result suggests the presence of windfall effects. We also show complex interactions (antagonism or synergy) between economic and environmental performances in adoption decisions, and heterogeneous effects depending on the type of farming.

Sessile serrated lesion prevalence and factors associated with their detection: a post-hoc analysis of a multinational randomized controlled trial from Asia.

Sessile serrated lesions (SSLs) are associated with an increased risk of colorectal cancer. Data on the prevalence of SSLs in Asia are limited. We performed this study to estimate the prevalence of SSLs in Asia and to explore endoscopic factors that are associated with SSL detection. This is a post-hoc analysis of a multicenter randomized controlled trial from four Asian countries/regions that compared adenoma detection rates using linked-color imaging (LCI) and white-light imaging. Colonoscopies were performed in an average-risk population for screening, diagnostic examination, or polyp surveillance. Patients with SSLs were compared against those without SSLs to evaluate for possible predictors of SSL detection using Firth's logistic regression. 2898 participants (mean age 64.5 years) were included in the analysis. The estimated prevalence of SSLs was 4.0% (95%CI 3.4%-4.8%), with no sex or age group differences. On multivariable analysis, use of LCI (adjusted odds ratio [aOR] 1.63, 95%CI 1.10-2.41), experienced endoscopists (aOR 1.94, 95%CI 1.25-3.00), use of transparent cap (aOR 1.75, 95%CI 1.09-2.81), and longer withdrawal time (aOR 1.06, 95%CI 1.03-1.10) were independently associated with SSL detection. Synchronous adenoma detection (aOR 1.89, 95%CI 1.20-2.99) was also predictive of SSL detection. The prevalence of SSLs in Asia is 4.0%. Use of LCI or a transparent cap, greater endoscopist experience, and longer withdrawal time were all associated with increased SSL detection.

Genetic polymorphisms linked to extreme postorthodontic external apical root resorption in Koreans

BackgroundExternal apical root resorption (EARR) is a common undesirable outcome of orthodontic treatment, this study aimed to identify genetic polymorphisms associated with the susceptibility to extreme orthodontic-induced EARR in a Korean population using extreme phenotype analysis sampling.MethodsGenomic DNA was isolated from the saliva of 77 patients who underwent orthodontic treatment involving two maxillary premolar extractions. The patients were divided into two groups based on EARR values measured on periapical radiographs: The significant resorption group (SG, EARR ≥ 4 mm) and the normal group (NG, EARR < 2 mm). In the NG group, patients with EARR < 1 mm were named the non-resorption group (NonG). Targeted next-generation sequencing was performed using the screened single nucleotide polymorphisms (SNPs), and firth logistic regression analysis was used to determine genetic associations with EARR. Haplotype-based association analysis was performed for specific SNPs.ResultsSNPs related to genes TNFSF11, TNFRSF11B, WNT3A, SFRP2, LRP6, P2RX7, and LRP1 were found to be significantly associated with severe EARR (p < 0.05, pre-Bonferroni correction p-values). Additionally, the haplotype CCA of rs17525809, rs208294, and rs1718119 P2RX7 had a higher frequency in the SG group.ConclusionExtreme phenotype analysis has identified eleven SNPs related to genes TNFSF11, TNFRSF11B, WNT3A, SFRP2, LRP6, P2RX7, and LRP1 that are associated with severe root resorption in the Korean population. These findings will contribute to the development of predictive diagnostic tools for identifying severe root resorption that may occur during orthodontic treatment.

Association between rare pathogenic variants in established cancer risk genes and the diagnosis of single and multiple common cancers: A UK Biobank study.

10505 Background: Much of our understanding of cancer risk attributable to rare pathogenic variants (RPV) is derived from family-based and case-only cohort studies, which may be limited by ascertainment bias. We sought to identify associations between RPVs and cancer diagnoses in a large population-based study. Methods: We conducted a case-control study using the UK Biobank. We performed gene-based aggregate testing to examine the relationship between RPVs (defined as pathogenic or likely pathogenic variants) in 96 genes implicated in cancer risk and the diagnosis of 11 common cancers using the combined optimal unified sequence kernel association test (SKAT-O). Odds ratios (OR) and 95% confidence intervals (CI) were then calculated using Firth logistic regression. Results were adjusted for age, sex and genetic ancestry. Bonferroni-adjusted p-values were used to determine statistical significance. Variant pathogenicity was determined by American College of Medical Genetics criteria. Results: We identified 24 genes in which RPVs were statistically significantly associated with at least one of 11 common cancers among 183,626 individuals. The presence of an RPV in one of these 24 genes was associated with increased odds of one cancer (OR 1.8; 95% CI: 1.7-2.0), and multiple cancers (OR 2.5; 95% CI: 2.2-2.9). Conclusions: This large population-based study identified 24 established cancer risk genes in which RPVs were associated with common cancers. We identified both known and novel associations between cancer and RPVs. Some associations—i.e. renal/pancreas and MEN1—may be due to ascertainment and/or misclassification bias. We also show that individuals with RPVs in cancer risk genes not only have higher odds of one cancer diagnosis, but also multiple cancers.[Table: see text]

Immigration and Physical Discipline of Children: The Influence of Generational Status and Culture

ABSTRACTThis research examines whether physical punishment towards children in Méxican immigrant and native‐born Latinx families of Mexican heritage households varies across immigrant generational status and if physical punishment is associated with important measures of culture: familismo, traditional machismo, acculturation to the United States and enculturation to México. Data from a sample of households in El Paso County, Texas, are analysed using Firth logistic regression. Findings show that physical punishment is lowest in first‐generation immigrant households but, in sharp contrast, highest in 1.5‐generation immigrant households, suggesting the need for more precise measurement of immigration status as such differentiation can be masked with a more general approach to measuring immigrant generation. Findings also indicate that enculturation to México is protective towards physical punishment, while measures of acculturation, familismo and traditional machismo are not associated with this behaviour in multivariate models.

Evaluating rural health outcomes: A methodological approach using population-level data.

The sustainability of rural surgical and obstetrical facilities depends on their efficacy and quality of care, which are difficult to measure in a rural context. In an evaluation of rural practice, it is often the case that the only comparators are larger referral facilities, for which facility-level comparisons are difficult due to differences in population demographics, acuity of patients, and services offered. This publication outlines these limitations and highlights a best-practice approach to making facility-level comparisons using population-level data, risk stratification, tests of noninferiority, and Firth logistic regression analysis. This includes an investigation of minimum sample-size requirements through Monte Carlo power analysis in the context of low-acuity rural surgical care. Monte Carlo power analysis was used to estimate the minimum sample size required to achieve a power of 0.8 for both logistic regression and Firth logistic regression models that compare the proportion of surgical adverse events against facility type, among other confounders. We provide guidelines for the implementation of a recommended methodology that uses risk stratification, Firth penalized logistic regression, and tests of noninferiority. We illustrate limitations in facility-level comparison of surgical quality among patients undergoing one of four index procedures including hernia repair, colonoscopy, appendectomy, and cesarean delivery. We identified minimum sample sizes for comparison of each index procedure that fluctuate depending on the level of risk stratification used. The availability of administrative data can provide an adequate sample size to allow for facility-level comparisons in surgical quality, at the rural level and elsewhere. When they are made appropriately, these comparisons can be used to evaluate the efficacy of general practitioners and nurse practitioners in performing low-acuity procedures.