Tag: statistics

Am J Med Genet B Neuropsychiatr Genet. 2022 Jul 15. doi: 10.1002/ajmg.b.32907. Online ahead of print.

ABSTRACT

Recent genome-wide association studies of mood instability (MOOD) have found significant positive genetic correlation with major depression (DEP) and weak correlations with other psychiatric disorders. We investigated the polygenic overlap between MOOD and psychiatric disorders beyond genetic correlation to better characterize putative shared genetic determinants. GWAS summary statistics for schizophrenia (SCZ, n = 105,318), bipolar disorder (BIP, n = 413,466), DEP (n = 450,619), attention-deficit hyperactivity disorder (ADHD, n = 53,293), and MOOD (n = 363,705) were analyzed using the bivariate causal mixture model and conjunctional false discovery rate methods. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (r_g = 0.10-0.62). Of 10.4 K genomic variants influencing MOOD, 4 K-9.4 K influenced psychiatric disorders. Furthermore, MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25. Fifty-three jointly associated loci were overlapping across two or more disorders, seven of which had discordant effect directions on psychiatric disorders. Genes mapped to loci associated with MOOD and all four disorders were enriched in a single gene-set, “synapse organization.” The extensive polygenic overlap indicates shared molecular underpinnings across MOOD and psychiatric disorders. However, distinct patterns of genetic correlation and effect directions may relate to differences in the core clinical features of each disorder.

PMID:35841185 | DOI:10.1002/ajmg.b.32907

Clin Pharmacol Ther. 2022 Jul 15. doi: 10.1002/cpt.2712. Online ahead of print.

ABSTRACT

Vericiguat, a novel stimulator of soluble guanylate cyclase (sGC), is indicated for the treatment of patients following a hospitalization for heart failure or need for outpatient IV diuretics, with symptomatic chronic heart failure and ejection fraction less than 45%. Pharmacokinetic (PK) data from the phase II trial SOCRATES-REDUCED (SOluble guanylate Cyclase stimulatoR in heArT failurE Study) and the phase III trial VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) were used to characterize vericiguat PK. A total of 8,092 concentration records from 2,321 participants (362 from SOCRATES-REDUCED and 1,959 from VICTORIA) were utilized for the development of the population PK (PPK) model. The final PK model was a one-compartment model with first-order absorption and linear elimination. Baseline body weight and time-varying body weight were identified as statistically significant covariates affecting apparent clearance (CL/F) and volume of distribution (V_c ), respectively. Age, sex, race, bilirubin, estimated glomerular filtration rate (eGFR), and albumin did not affect vericiguat PK. Baseline disease-related factors, such as left ventricular ejection fraction, New York Heart Association (NYHA) class, and N-terminal pro B-type natriuretic peptide (NT-proBNP), also did not influence vericiguat PK. Since vericiguat is a titrated drug, the impact of vericiguat PK on the titration to and maintenance of the target dose in VICTORIA was assessed. The distribution of steady-state doses in VICTORIA was similar across CL/F quartiles, suggesting that the ability to reach and maintain dosing at the target 10 mg dose was not related to vericiguat exposure.

PMID:35841202 | DOI:10.1002/cpt.2712

Probl Endokrinol (Mosk). 2022 Jun 16;68(3):113-120. doi: 10.14341/probl13129.

ABSTRACT

BACKGROUND: Type 2 diabetes mellitus (DM2) in men is associated with a high incidence of hypogonadism. Testosterone is a steroid hormone and one of the final metabolites of steroidogenesis, which causes interest in assessing the content of key steroid hormones, their precursors and metabolites in hypogonadal and eugonadal men with T2DM.

AIMS: Assessment of the features of steroidogenesis in men with hypogonadism in T2DM using tandem mass spectrometry.

MATERIALS AND METHODS: A full-design, cross-sectional, screening, single-center, non-interventional study included men with T2DM, who were he was treated in Endocrinology Research Centre, Moscow. The study was conducted from October 2021 to January 2022. Medical history assessment, physical examination with determination of body mass index (BMI), measurement of key steroid hormones, their precursors and metabolites by isotope dilution liquid chromatography/tandem mass spectrometry, glycated hemoglobin (HbA1c) were performed. The groups were compared using the Mann-Whitney U-test for quantitative indicators and χ² with Yates’ correction for qualitative ones. Correlation analysis was performed by the Spearman correlation method. When determining the criterion of statistical significance, the Bonferroni correction was applied.

RESULTS: Patients with hypogonadism had statistically significantly more pronounced obesity compared with eugonadal men. In a comparative analysis of patients, depending on the presence of hypogonadism, there were statistically significantly lower levels of androgen precursors 17-hydroxypregnenolone and 17-hydroxyprogesterone in hypogonadal men. At the same time, a positive statistically significant correlation was found between total testosterone and 17-hydroxyprogesterone. In addition, 17-hydroxyprogesterone, although to a lesser extent, but positively correlated with other androgens – androstenedione (r=0,328; p<0,001) and dehydroepiandrosterone (r=0,183; p=0,004). >< 0,001) and dehydroepiandrosterone (r=0,183; p=0,004).

CONCLUSIONS: In this investigation the prevalence of male hypogonadism in type 2 diabetes, determined by high-precision tandem mass spectrometry, was 69,5%. There was no effect of the disease on the mineralocorticoid and glucocorticoid links of adrenal steroidogenesis. Hypogonadism was associated with decreased levels of a number of testosterone precursors. The most significant of them was 17-hydroxyprogesterone, which can be considered as a marker of testicular steroidogenesis.

PMID:35841175 | DOI:10.14341/probl13129

Probl Endokrinol (Mosk). 2022 Apr 12;68(3):93-104. doi: 10.14341/probl12854.

ABSTRACT

BACKGROUND: Cushing’s disease (CD) is a rare disorder of a persistent cortisol excess caused by ACTH-secreting pituitary tumor (corticotropinoma). Transsphenoidal surgery (TSS) is a treatment of choice for СD, which effectiveness range is from 70 to 90%. Recurrence rate after successful treatment is about 25%. If surgical treatment is unsuccessful or recurrence appear, radiation treatment is the next therapeutic option, which effectiveness range is also 90%, but the hypopituitarism rate as side effect of treatment is higher. Preoperative predictors of remission and recurrence are still unexplored what leads to further investigations.

AIM: Analysis of remission and recurrence rates of pediatric CD after successful treatment according to preoperative MRI and therapeutic option.

MATERIALS AND METHODS: We conducted a retrospective analysis of 90 pediatric patients with CD who were observed between 1992 and 2020 at the Endocrinology Research Centre.

RESULTS: The most common clinical symptoms of CD were weight gain [94%] and growth retardation [72%]. Pituitary tumor was detected on radiological imaging in 53/90 patients [59%], there were no signs of visible adenoma in 37/90 of patients [41%]. 63 of 90 patients underwent TSS (70%), 27 patients underwent radiosurgery (30%). Remission rate after TSS was 71% [45/63], after radiosurgery – 85% [23/27]. There were no significant differences in remission rates after radical treatment according to preoperative MRI results (P=0.21 after TSS and P=0.87 after radiosurgery, х2 analysis). Recurrence after successful treatment was diagnosed in 10 patients. There were no significant differences in time to recurrence according to preoperative MRI results (P=0.055, х2 analysis). Time to recurrence was statistically different after TSS compared to radiosurgery (P=0.007, Kaplan-Meier analysis) and in the group with developed adrenal insufficiency in the early postoperative period (P=0.04, Kaplan-Meier analysis). Analysis of side effect of treatment showed that the frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery (р<0.01, Kruskel-Wallis ANOVA test). Diabetes insipidus was diagnosed only after TSS.

CONCLUSION: Results of our study didn`t allow to use MRI-results as predictor of effectiveness treatment in pediatric CD. Therapeutic option has an impact on time to recurrence, not on recurrence rates. The frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery compared to TSS. Further studies are needed to identify predictors of remission and recurrence in CD.>< 0.01, Kruskel-Wallis ANOVA test). Diabetes insipidus was diagnosed only after TSS.

CONCLUSION: Results of our study didn`t allow to use MRI-results as predictor of effectiveness treatment in pediatric CD. Therapeutic option has an impact on time to recurrence, not on recurrence rates. The frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery compared to TSS. Further studies are needed to identify predictors of remission and recurrence in CD.

PMID:35841173 | DOI:10.14341/probl12854

Probl Endokrinol (Mosk). 2022 Mar 8;68(3):30-43. doi: 10.14341/probl12844.

ABSTRACT

BACKGROUND: Nowadays, the Republic of Belarus belongs to the countries with sufficient iodine supply, which made it possible to reduce the incidence of non-toxic goiter and congenital hypothyroidism. However, even a slight change in iodine consumption influences the pattern of thyroid diseases. In addition to iodine deficiency, other environmental conditions, as well as genetic factors, play a significant role in the etiology of thyroid diseases.

AIM: To analyze the dynamics of the main epidemiological indicators of benign thyroid diseases from 2009 to 2019 in the adult population of the Republic of Belarus, using the data of official state statistics.

MATERIALS AND METHODS: The indicators of the incidence and prevalence of benign thyroid diseases were studied on the basis of state statistics for 2009-2019. To analyze the dynamics of the studied indicators, regression analysis was used with the construction of linear and polynomial models.

RESULTS: A decrease in the incidence and prevalence of diffuse euthyroid goiter and an increase in the incidence and prevalence of nodular euthyroid goiter, thyroiditis, acquired hypothyroidism, Graves’ disease, as well as the incidence of nodular toxic goiter were revealed.

CONCLUSION: Obtained data indicate, that there is an increase in the prevalence of most of the studied thyroid diseases, despite the adequate iodine supply. The above justifies the need for further study of the causes of the identified trends, as well as the necessity of developing new methods of diagnosis and treatment of thyroid diseases.

PMID:35841166 | DOI:10.14341/probl12844

Mol Ther. 2022 Jul 14:S1525-0016(22)00429-4. doi: 10.1016/j.ymthe.2022.07.008. Online ahead of print.

ABSTRACT

Simultaneous inhibition of interleukin-6 (IL-6) and interleukin-8 (IL-8) signaling diminishes cancer cell migration, and combination therapy has recently been shown to synergistically reduce metastatic burden in a preclinical model of triple negative breast cancer. Here, we have engineered two novel bispecific antibodies that target the IL-6 and IL-8 receptors to concurrently block the signaling activity of both ligands. We demonstrate that a first-in-class bispecific antibody design has promising therapeutic potential, with enhanced selectivity and potency compared to monoclonal antibody and small molecule drug combinations in both cellular and animal models of metastatic triple negative breast cancer. Mechanistic characterization revealed that our engineered bispecific antibodies have no impact on cell viability, but profoundly reduce the migratory potential of cancer cells; hence they constitute a true anti-metastatic treatment. Moreover, we demonstrate that our antibodies can be readily combined with standard of care anti-proliferative drugs to develop effective anti-cancer regimens. Collectively, our work establishes an innovative metastasis-focused direction for cancer drug development.

PMID:35841152 | DOI:10.1016/j.ymthe.2022.07.008

Biophys J. 2022 Jul 14:S0006-3495(22)00554-9. doi: 10.1016/j.bpj.2022.07.008. Online ahead of print.

ABSTRACT

Cholesterol plays a unique role in the regulation of membrane organization and dynamics by modulating the membrane phase transition at the nanoscale. Unfortunately, due to their small sizes and dynamic nature, the effects of cholesterol-mediated membrane nanodomains on membrane dynamics remain elusive. Here, using ultrahigh-speed single-molecule tracking with advanced optical microscope techniques, we investigate the diffusive motion of single phospholipids in the live cell plasma membrane at the nanoscale and its dependency on the cholesterol concentration. We find that both saturated and unsaturated phospholipids undergo anomalous subdiffusion on the length scale of 10-100 nm. The diffusion characteristics exhibit considerable variations in space and in time, indicating that the nanoscopic lipid diffusion is highly heterogeneous. Importantly, through the statistical analysis, apparent dual-mobility subdiffusion is observed from the mixed diffusion behaviors. The measured subdiffusion agrees well with the hop diffusion model that represents a diffuser moving in a compartmentalized membrane created by the cytoskeleton meshwork. Cholesterol depletion diminishes the lipid mobility with an apparently smaller compartment size and a stronger confinement strength. Similar results are measured with temperature reduction, suggesting that the more heterogeneous and restricted diffusion is connected to the nanoscopic membrane phase transition. Our conclusion supports the model that cholesterol depletion induces the formation of gel-phase, solid-like membrane nanodomains. These nanodomains undergo restricted diffusion and act as diffusion obstacles to the membrane molecules that are excluded from the nanodomains. This work provides the experimental evidence that the nanoscopic lipid diffusion in the cell plasma membrane is heterogeneous and sensitive to the cholesterol concentration and temperature, shedding new light on the regulation mechanisms of nanoscopic membrane dynamics.

PMID:35841144 | DOI:10.1016/j.bpj.2022.07.008

Res Synth Methods. 2022 Jul 15. doi: 10.1002/jrsm.1592. Online ahead of print.

ABSTRACT

Meta-analysis is a widely used methodology to combine evidence from different sources examining a common research phenomenon, to obtain a quantitative summary of the studied phenomenon. In the medical field, multiple studies investigate the effectiveness of new treatments and meta-analysis is largely performed to generate the summary (average) treatment effect. In the meta-analysis of aggregate continuous outcomes measured in a pretest-posttest design using differences in means as the effect measure, a plethora of methods exist: analysis of final (follow-up) scores, analysis of change scores and analysis of covariance (ANCOVA). Specialised and general purpose statistical software is used to apply the various methods, yet, often the choice among them depends on data availability and statistical affinity. We present a new web-based tool, MA-cont:pre/post effect size, to conduct meta-analysis of continuous data assessed pre- and post-treatment using the aforementioned approaches on aggregate data and a more flexible approach of generating and analysing pseudo individual participant data (IPD). The interactive web environment, available by R Shiny, is used to create this free-to-use statistical tool, requiring no programming skills by the users. A basic statistical understanding of the methods running in the background is a prerequisite and we encourage the users to seek advice from technical experts when necessary. This article is protected by copyright. All rights reserved.

PMID:35841123 | DOI:10.1002/jrsm.1592

Acta Neurol Scand. 2022 Jul 15. doi: 10.1111/ane.13669. Online ahead of print.

ABSTRACT

OBJECTIVES: Unbiased and full disclosure of trial results is vital to evidence-based medicine. Non-publication and selective publication leads to publication bias and unrealistic risk-benefit ratio. In the present study, we aim to determine the publication rate of clinical trials related to neurology registered with the Clinical Trial Registry of India (CTRI), compare the characteristics of published and unpublished trials, and evaluate the adherence of investigators to ethics-approved criteria and outcomes.

MATERIALS AND METHODS: A cross-sectional search using the keyword “neurology” was carried out in CTRI registry. Two independent investigators searched Pubmed, Medline, Scopus, and Google Scholar for published manuscripts. The final literature search occurred in November 2021.

RESULTS: Out of 325 trials, 102 trials were published (31.4%). Ninety-one trials were beyond 3 years of expected time of trial completion and were still unpublished. Randomized trials had a slightly higher publication rate than non-randomized ones (56% vs. 46%, p = .223); however the difference was not statistically significant. Majority of trials sponsored by pharmaceutical companies were not published, while majority of those sponsored by non-pharmaceutical institutions were published (34.5% vs. 69.3%, p < .001). Feedback to CTRI about trial status was particularly poor (31.5% – informed vs. 68.5% – not informed, p < .001). 52 (50.9%) and 65 (63.7%) of the 102 published trials had changed the registered inclusion and exclusion criteria, respectively, in the CTRI registry compared to those in the published manuscript. In 29 (28.3%) of the 102 trials, the primary outcome did not match with that registered in the CTRI and in 73 (57.8%) trials, the secondary outcomes did not match.

CONCLUSION: A large proportion of neurology registered trials are still unpublished, with a majority of pharmaceutical company-sponsored trials not being published. There is scope for improving the provisions in CTRI for enlisting trial results, that may prevent publication bias and also ensure the investigators adhere to the pre-specified ethics approved trial procedures and outcomes.

PMID:35841133 | DOI:10.1111/ane.13669

Canine Med Genet. 2022 Jul 15;9(1):10. doi: 10.1186/s40575-022-00122-9.

ABSTRACT

Lymphoma is the second most common cancer affecting Golden Retrievers and is hypothesized to arise through a complex interaction of genetic and environmental factors. The aim of this nested case-control study was to investigate the association between potential environmental pollutant sources and lymphoma risk among Golden Retrievers participating in the Golden Retriever Lifetime Study. Forty-nine Golden Retrievers with non-cutaneous lymphoma and 98 Golden Retrievers without a history of cancer matched by age, sex and neuter status were selected from the Golden Retriever Lifetime Study cohort. Geographic proximity between each dog’s primary residence and nine potential sources of environmental pollution was determined. In addition, the average annual ozone and airborne fine particulate matter levels for each dog’s county of residence and owner-reported secondhand smoke exposure were evaluated. Environmental pollution sources of interest included chemical plants, municipal dumps, manufacturing plants, incineration plants, railroad embankment tracks, landfills, coal plants, high-voltage transmission lines, and nuclear power plants. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each exposure of interest. Subgroup analyses were conducted to evaluate whether associations differed among 1) dogs with multicentric lymphoma, 2) dogs with B-cell lymphoma, and 3) dogs with T-cell lymphoma. No variables reached statistical significance when evaluating all cases together. However, cumulative exposure burden (household proximity to 3 or more pollution sources) approached significance within the multicentric lymphoma subgroup (OR = 2.60, 95%CI 0.99-6.86, p-value = 0.053). Patterns emerged among B- and T-cell subgroups, but none reached statistical significance. Ongoing research is warranted to discern if different environmental mechanisms may be driving B- and T-cell lymphoma immunophenotypes, consistent with previously reported regional differences in subtype prevalence.

PMID:35841115 | DOI:10.1186/s40575-022-00122-9