Category: Statistics

Hum Reprod. 2022 Jan 11:deab285. doi: 10.1093/humrep/deab285. Online ahead of print.

ABSTRACT

STUDY QUESTION: Do fertility drugs increase the risk of thyroid cancer among infertile women?

SUMMARY ANSWER: The use of most types of fertility drugs was not associated with an increased risk of thyroid cancer.

WHAT IS KNOWN ALREADY: The incidence of thyroid cancer is higher for women than men, especially during reproductive years, indicating that reproductive hormones may be involved in the development of thyroid cancer. Only a few previous studies have examined the association between the use of fertility drugs and incidence of thyroid cancer and the results are inconclusive.

STUDY DESIGN, SIZE, DURATION: A retrospective, population-based cohort study including all 146 024 infertile women aged 20-45 years and living in Denmark in the period 1995-2017. The women were followed from the date of entry in the cohort (i.e. date of first infertility diagnosis) until the occurrence of thyroid cancer or any other cancer (except non-melanoma skin cancer), death, emigration, total thyroidectomy or the end of follow-up (31 December 2018), whichever occurred first. The median length of follow-up was 11.3 years.

PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 167 women were diagnosed with thyroid cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), thyroid cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for thyroid cancer overall and for papillary thyroid cancer.

MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for the calendar year of infertility diagnosis, the highest obtained level of education, parity status, obesity or thyroid disease and mutual adjustment for other registered fertility drugs, no marked associations were observed between the use of clomiphene citrate, hCG, gonadotropins or GnRH receptor modulators and risk of overall or papillary thyroid cancer. However, ever use of progesterone was associated with an increased rate of both overall (HR 1.63; 95% CI 1.07-2.48) and papillary (HR 1.66, 95% CI 1.04-2.65) thyroid cancer after mutual adjustment for other specific fertility drugs. For most specific fertility drugs, we observed a tendency toward higher associations with thyroid cancer within the first 5 years after the start of drug use than after 5 years from the start of use. No marked associations were detected according to the cumulative dose for any of the specific fertility drugs.

LIMITATIONS, REASONS FOR CAUTION: Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of thyroid cancer cases. Although we were able to adjust for a number of potential confounders, residual and unmeasured confounding may potentially have affected the observed associations, as we could not adjust for some factors that may influence the association between fertility drugs and thyroid cancer, including age at menarche and BMI.

WIDER IMPLICATIONS OF THE FINDINGS: Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and thyroid cancer incidence, we observed a modest increased thyroid cancer incidence after the use of progesterone. However, we cannot rule out that this is a chance finding and the potential association between the use of progesterone and thyroid cancer should therefore be investigated further in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of infertility.

STUDY FUNDING/COMPETING INTEREST(S): The study was supported by research grants from the Jascha Foundation and the Aase and Ejner Danielsens Foundation. B.N. received honoraria and/or non-financial support by Gedeon Richter Nordics AB, IBSA Nordic APS and Merck KGAA. The remaining authors have no competing interests.

TRIAL REGISTRATION NUMBER: N/A.

PMID:35020884 | DOI:10.1093/humrep/deab285

J Am Med Inform Assoc. 2022 Jan 10:ocab290. doi: 10.1093/jamia/ocab290. Online ahead of print.

ABSTRACT

OBJECTIVE: Evidence synthesis teams, physicians, policy makers, and patients and their families all have an interest in following the outcomes of clinical trials and would benefit from being able to evaluate both the results posted in trial registries and in the publications that arise from them. Manual searching for publications arising from a given trial is a laborious and uncertain process. We sought to create a statistical model to automatically identify PubMed articles likely to report clinical outcome results from each registered trial in ClinicalTrials.gov.

MATERIALS AND METHODS: A machine learning-based model was trained on pairs (publications known to be linked to specific registered trials). Multiple features were constructed based on the degree of matching between the PubMed article metadata and specific fields of the trial registry, as well as matching with the set of publications already known to be linked to that trial.

RESULTS: Evaluation of the model using known linked articles as gold standard showed that they tend to be top ranked (median best rank = 1.0), and 91% of them are ranked in the top 10.

DISCUSSION: Based on this model, we have created a free, public web-based tool that, given any registered trial in ClinicalTrials.gov, presents a ranked list of the PubMed articles in order of estimated probability that they report clinical outcome data from that trial. The tool should greatly facilitate studies of trial outcome results and their relation to the original trial designs.

PMID:35020887 | DOI:10.1093/jamia/ocab290

Clin Exp Immunol. 2021 Nov 18:uxab015. doi: 10.1093/cei/uxab015. Online ahead of print.

ABSTRACT

Although there is an ever-increasing number of disease-modifying treatments for relapsing multiple sclerosis (MS), few appear to influence COVID-19 severity. There is concern about the use of anti-CD20-depleting monoclonal antibodies, due to the apparent increased risk of severe disease following SARS-CoV-2 infection and inhibition of protective anti-COVID-19 vaccine responses. These antibodies are given as maintenance infusions/injections and cause persistent depletion of CD20+ B cells, notably memory B cell populations that may be instrumental in the control of relapsing MS. However, they also continuously deplete immature and mature/naïve B cells that form the precursors for infection-protective antibody responses, thus blunting vaccine responses. Seroconversion and maintained SARS-CoV-2 neutralizing antibody levels provide protection from COVID-19. However, it is evident that poor-seroconversion occurs in the majority of individuals following initial and booster COVID-19 vaccinations, based on standard 6-monthly dosing intervals. Seroconversion may be optimized in the anti-CD20-treated population by vaccinating prior to treatment-onset or using extended/delayed interval dosing (3-6 month extension to dosing interval) in those established on therapy, with B cell monitoring until (1-3%) B cell repopulation occurs prior to vaccination. Some people will take more than a year to replete and therefore protection may depend on either the vaccine-induced T cell responses that typically occur or may require prophylactic, or rapid post-infection therapeutic, antibody or small molecule anti-viral treatment to optimise protection against COVID-19. Further studies are warranted to demonstrate the safety and efficacy of such approaches and whether or not immunity wanes prematurely as has been observed in the other populations.

PMID:35020857 | DOI:10.1093/cei/uxab015

Bioinformatics. 2022 Jan 10:btac024. doi: 10.1093/bioinformatics/btac024. Online ahead of print.

ABSTRACT

MOTIVATION: Polygenic risk score (PRS) has been widely exploited for genetic risk prediction due to its accuracy and conceptual simplicity. We introduce a unified Bayesian regression framework, NeuPred, for PRS construction, which accommodates varying genetic architectures and improves overall prediction accuracy for complex diseases by allowing for a wide class of prior choices. To take full advantage of the framework, we propose a summary-statistics-based cross-validation strategy to automatically select suitable chromosome-level priors, which demonstrates a striking variability of the prior preference of each chromosome, for the same complex disease, and further significantly improves the prediction accuracy.

RESULTS: Simulation studies and real data applications with seven disease datasets from the Wellcome Trust Case Control Consortium cohort and eight groups of large-scale genome-wide association studies demonstrate that NeuPred achieves substantial and consistent improvements in terms of predictive r2 over existing methods. In addition, NeuPred has similar or advantageous computational efficiency compared with the state-of-the-art Bayesian methods.

AVAILABILITY: The R package implementing NeuPred is available at https://github.com/shuangsong0110/NeuPred.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:35020805 | DOI:10.1093/bioinformatics/btac024

Cardiovasc Res. 2022 Jan 10:cvab375. doi: 10.1093/cvr/cvab375. Online ahead of print.

ABSTRACT

 : Cardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar APDs.

AIMS: To assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells.

METHODS AND RESULTS: APD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25ms (mean±SD) in 17 hearts with a mean inter-quartile range (IQR) of 53 ± 17ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4,471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX and INaK.

CONCLUSIONS: Modelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarisation despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.

TRANSLATIONAL PERSPECTIVE: We show that single myocytes from the same region of a heart have highly variable electrophysiology and different responses to ion-channel blocking drugs because of even higher inter-cell variation in ion-channel activity. Our data demonstrate that it is the relative activity of a single ion channel comparted to others that determines electrophysiological stability in the heart. Therefore, predisposition to arrhythmias from genetic or environmental causes is not due to up- or down-regulation of single ion-channels, but instead disrupted patterns of co-expression. An alternative treatment strategy therefore is to manipulate other ion-channels in the network to restore a stable co-expression pattern.

PMID:35020837 | DOI:10.1093/cvr/cvab375

Am J Epidemiol. 2022 Jan 7:kwab300. doi: 10.1093/aje/kwab300. Online ahead of print.

ABSTRACT

Rural-urban differences in maternal mortality ratios (MMR) in the United States have been difficult to measure in recent years due to the incremental adoption of a pregnancy status checkbox on death certificates. Using 1999-2017 mortality and birth data, we examined the impact of the pregnancy checkbox on MMRs by rural-urban residence (large urban, medium/small urban, rural), using log-binomial regression models to predict trends as if all states had adopted the checkbox as of 1999. Implementation of the checkbox resulted in an average estimated increase of 7.5 maternal deaths per 100,000 live births (95% CI: 6.3, 8.8) in large urban areas (76% increase), 11.6 (95% CI: 9.6, 13.6) in medium/small urban areas (113% increase), and 16.6 (95% CI: 12.9, 20.3) in rural areas (107% increase), compared with MMRs prior to the checkbox. Assuming all states had the checkbox as of 1999, demographic-adjusted predicted MMRs increased in rural, declined in large urban, and did not change in medium/small urban areas. However, trends and urban-rural differences were substantially attenuated when analyses were limited to direct/specific causes of maternal death, which are likely subject to less misclassification. Accurate ascertainment of maternal deaths, particularly in rural areas, is important for reducing disparities in maternal mortality.

PMID:35020799 | DOI:10.1093/aje/kwab300

Am J Epidemiol. 2022 Jan 11:kwab297. doi: 10.1093/aje/kwab297. Online ahead of print.

ABSTRACT

Racial residential segregation is associated with multiple adverse health outcomes in Black individuals. Yet, the influence of structural racism and racial residential segregation on brain aging is less understood. In this study, we investigate the association between cumulative exposure to racial residential segregation over 25 years (1985-2010) of young adulthood, measured by the Getis-Ord Gi*-statistic, and year 25 measures of brain volume in midlife (cerebral, gray matter, white matter, and hippocampal volumes). We studied 290 Black participants with available brain imaging data who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study. CARDIA originally recruited 2637 Black participants aged 18 to 30 years old from 4 field centers across the United States. We conducted analyses using marginal structural models, incorporating inverse probability weighting and inverse censoring weighting. We found that compared to low/medium segregation, greater cumulative exposure to residential segregation throughout young adulthood was associated with smaller brain volumes in general (e.g. β for cerebral volume: -0.08 [95% CI]: [-0.15, -0.02]) and with a more pronounced reduction in hippocampal volume, though results were not statistically significant. Our findings suggest that exposure to segregated neighborhoods may be associated with worse brain aging.

PMID:35020781 | DOI:10.1093/aje/kwab297

Am J Clin Nutr. 2022 Jan 10:nqab428. doi: 10.1093/ajcn/nqab428. Online ahead of print.

ABSTRACT

BACKGROUND: Longer-term consumption of saturated fatty acid (SFA)-reduced, monounsaturated fatty acid (MUFA)-enriched dairy products have been reported to improve fasting flow-mediated vasodilation (FMD). Yet, their impact on endothelial function in the postprandial state warrants investigation.

OBJECTIVES: To compare the impact of a fatty acid (FA)-modified with a conventional (control) dairy diet on the postprandial %FMD (primary outcome) and systemic cardiometabolic responses to representative meals, and retrospectively explore whether treatment effects differ by apolipoprotein (APO)E or endothelial nitric oxide synthase (eNOS) Glu298Asp gene polymorphisms.

METHODS: In a crossover-design randomized controlled study, 52 adults with moderate cardiovascular disease risk consumed dairy products [38% total energy intake (%TE) from fat: FA-modified (target: 16%TE SFAs; 14%TE MUFAs) or control (19%TE SFAs; 11%TE MUFAs)] for 12-wk, separated by an 8-wk washout. Blood sampling and FMD measurements (0-480 min) were performed pre- and post-intervention after sequential mixed meals that were representative of the assigned dairy diets (0 min; ∼50 g fat; 330 min; ∼30 g fat).

RESULTS: Relative to pre-intervention (∆), the FA-modified dairy diet and meals (treatment) attenuated the increase in the incremental AUC (iAUC), but not AUC, for the %FMD response observed with the conventional treatment (-135 ± 69 vs + 199 ± 82% x min; P = 0.005). The ∆ iAUC, but not AUC, for the apoB response decreased after FA-modified yet increased after the conventional treatment (-4 ± 3 vs + 3 ± 3 mg/mL × min; P = 0.004). The ∆ iAUC decreased for total plasma SFAs (P = 0.003) and trans 18:1 (P < 0.0001) and increased for cis-MUFAs (P < 0.0001) following conventional, relative to the FA-modified treatment. No treatment x APOE- or eNOS-genotype interactions were evident for any outcome.

CONCLUSIONS: This study provides novel insights into the longer-term effects of FA-modified dairy food consumption on postprandial cardiometabolic responses. Clinical Trial Registry: Unique identifier: NCT02089035. URL: https://clinicaltrials.gov/ct2/show/NCT02089035.

PMID:35020795 | DOI:10.1093/ajcn/nqab428

PLoS One. 2022 Jan 12;17(1):e0262236. doi: 10.1371/journal.pone.0262236. eCollection 2022.

ABSTRACT

Wild birds can be colonized by bacteria, which are often resistant to antibiotics and have various virulence profiles. The aim of this study was to analyze antibiotic resistance mechanisms and virulence profiles in relation to the phylogenetic group of E. coli strains that were isolated from the GI tract of wildfowl. Out of 241 faecal samples, presence of E. coli resistant to a cephalosporin (ESBL/AmpC) was estimated for 33 isolates (13,7%). Based on the analysis of the coexistence of 4 genes encoding ESBLs/AmpC (blaCTX-M, blaTEM, blaSHV, blaAmpC) and class 1 and 2 integrons genes (intI1, intI2) a subset of two resistance profiles was observed among the investigated E. coli isolates carrying blaAmpC, blaSHV, and blaCTX-M, blaTEM, class 1 and 2 integrons, respectively. The E. coli isolates were categorized into 4 phylogenetic groups A (39.4%), B2 (24.25%), D (24.25%) and B1 (12.1%). The pathogenic B2 and D groups were mainly typical for the Laridae family. Among the 28 virulence factors (Vfs) detected in pathogenic phylogenetic groups B2 and D, 7 were exclusively found in those groups (sfa, vat, tosA, tosB, hly, usp, cnf), while 4 VFs (fecA, fyuA, irp2, kspMTII) showed a statistically significant association (P≤0.05) with phylogroups A and B1. Our results indicated that strains belonging to commensal phylogroups A/B1 possess extensive iron acquisition systems (93,9%) and autotransporters (60,6%), typical for pathogens, hence we suggest that these strains evolve towards higher levels of virulence. This study, which is a point assessment of the virulence and drug resistance potential of wild birds, confirms the importance of taking wild birds as a reservoir of strains that pose a growing threat to humans. The E. coli analyzed in our study derive from different phylogenetic groups and possess an arsenal of antibiotic resistance genes and virulence factors that contribute to their ability to cause diseases.

PMID:35020771 | DOI:10.1371/journal.pone.0262236

PLoS One. 2022 Jan 12;17(1):e0261946. doi: 10.1371/journal.pone.0261946. eCollection 2022.

ABSTRACT

Obesity is the most common nutritional disorder in dogs and it is associated with many comorbidities. Some obesity risk factors have already been established, however, the evaluation of the effect of different individual variables on weight loss induced by calorie restriction, although very important, is still poorly explored. The weight loss protocol can be updated and improved by more precise and adjusted equations throughout the weight loss program in the clinical routine practice. Therefore, the objective of this study was to analyze weight loss program dynamics in groups according to reproductive status, age, body size, and breed, as well as to define more accurately the amount of calories per target metabolic weight throughout the program. Data of 1,053 cases, presented between 2012 and 2019 at the Veterinary Hospital of the School of Veterinary Medicine and Animal Science of the University of São Paulo (FMVZ-USP) were retrospectively analyzed. A total of 77 obese dogs (body condition scores 8/9 or 9/9) of different ages, breeds, sizes, and reproductive status were selected. These dogs did not have any concomitant illnesses and successfully completed the weight loss program. Statistical analysis was performed and values of p≤0.05 were considered significant. The proposed weight loss program was based on an energy restriction protocol where daily energy intake (in kcal) was estimated as 70 kcal × target weight0.75. The target weight (TW) was defined as 80% of the animal’s current weight. The average calorie intake for weight loss (calories x target weight0.75) was lower for spayed females (62.36), differing from intact males (66.14) and neutered males (65.41), while intact females (63.66) showed intermediate values without differing between groups (p = 0.015). There were no differences between weight loss calories according to age (p = 0.473) or body size (p = 0.084), allowing the use of the same mathematical equation for intact and neutered dogs; for dogs older than 1 year and of different body sizes. Regarding the breed, the average calorie intake was lower (p = 0.002) in mixed breed dogs (61.54xTW0.75) when compared to obesity-prone purebred dogs (64.17xTW0.75) and other purebreds (65.27xTW0.75). It was concluded that spayed females and mixed breed dogs have greater difficulty in losing weight, that is, they need fewer calories per metabolic body weight for the weight loss program to succeed. A more accurate equation for energy requirement for weight loss can improve chances of success, therefore improving compliance and helping clinical management of obesity in dogs.

PMID:35020762 | DOI:10.1371/journal.pone.0261946