Category: Statistics

PLoS Genet. 2023 Jan 6;19(1):e1010573. doi: 10.1371/journal.pgen.1010573. Online ahead of print.

ABSTRACT

Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNAAla gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin, Bcl2l13, Ulk1, and Ulk2. Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2, while no statistically significant impact is seen for knockout of Parkin. This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes.

PMID:36608143 | DOI:10.1371/journal.pgen.1010573

PLoS Comput Biol. 2023 Jan 6;19(1):e1010820. doi: 10.1371/journal.pcbi.1010820. Online ahead of print.

ABSTRACT

In recent years, unsupervised analysis of microbiome data, such as microbial network analysis and clustering, has increased in popularity. Many new statistical and computational methods have been proposed for these tasks. This multiplicity of analysis strategies poses a challenge for researchers, who are often unsure which method(s) to use and might be tempted to try different methods on their dataset to look for the “best” ones. However, if only the best results are selectively reported, this may cause over-optimism: the “best” method is overly fitted to the specific dataset, and the results might be non-replicable on validation data. Such effects will ultimately hinder research progress. Yet so far, these topics have been given little attention in the context of unsupervised microbiome analysis. In our illustrative study, we aim to quantify over-optimism effects in this context. We model the approach of a hypothetical microbiome researcher who undertakes four unsupervised research tasks: clustering of bacterial genera, hub detection in microbial networks, differential microbial network analysis, and clustering of samples. While these tasks are unsupervised, the researcher might still have certain expectations as to what constitutes interesting results. We translate these expectations into concrete evaluation criteria that the hypothetical researcher might want to optimize. We then randomly split an exemplary dataset from the American Gut Project into discovery and validation sets multiple times. For each research task, multiple method combinations (e.g., methods for data normalization, network generation, and/or clustering) are tried on the discovery data, and the combination that yields the best result according to the evaluation criterion is chosen. While the hypothetical researcher might only report this result, we also apply the “best” method combination to the validation dataset. The results are then compared between discovery and validation data. In all four research tasks, there are notable over-optimism effects; the results on the validation data set are worse compared to the discovery data, averaged over multiple random splits into discovery/validation data. Our study thus highlights the importance of validation and replication in microbiome analysis to obtain reliable results and demonstrates that the issue of over-optimism goes beyond the context of statistical testing and fishing for significance.

PMID:36608142 | DOI:10.1371/journal.pcbi.1010820

Sci Adv. 2023 Jan 6;9(1):eabq5506. doi: 10.1126/sciadv.abq5506. Epub 2023 Jan 6.

ABSTRACT

Abnormal temperature caused by global climate change threatens the rice production. Defense signaling network for chilling has been uncovered in plants. However, less is known about repairing DNA damage produced from overwhelmed defense and its evolution during domestication. Here, we genetically identified a major QTL, COLD11, using the data-merging genome-wide association study based on an algorithm combining polarized data from two subspecies, indica and japonica, into one system. Rice loss-of-function mutations of COLD11 caused reduced chilling tolerance. Genome evolution analysis of representative rice germplasms suggested that numbers of GCG sequence repeats in the first exon of COLD11 were subjected to strong domestication selection during the northern expansion of rice planting. The repeat numbers affected the biochemical activity of DNA repair protein COLD11/RAD51A1 in renovating DNA damage under chilling stress. Our findings highlight a potential way to finely manipulate key genes in rice genome and effectively improve chilling tolerance through molecular designing.

PMID:36608134 | DOI:10.1126/sciadv.abq5506

Sci Adv. 2023 Jan 6;9(1):eade8898. doi: 10.1126/sciadv.ade8898. Epub 2023 Jan 6.

ABSTRACT

Atopic dermatitis (AD) is a chronic inflammatory skin condition increasing in industrial nations at a pace that suggests environmental drivers. We hypothesize that the dysbiosis associated with AD may signal microbial adaptations to modern pollutants. Having previously modeled the benefits of health-associated Roseomonas mucosa, we now show that R. mucosa fixes nitrogen in the production of protective glycerolipids and their ceramide by-products. Screening EPA databases against the clinical visit rates identified diisocyanates as the strongest predictor of AD. Diisocyanates disrupted the production of beneficial lipids and therapeutic modeling for isolates of R. mucosa as well as commensal Staphylococcus. Last, while topical R. mucosa failed to meet commercial end points in a placebo-controlled trial, the subgroup who completed the full protocol demonstrated sustained, clinically modest, but statistically significant clinical improvements that differed by study site diisocyanate levels. Therefore, diisocyanates show temporospatial and epidemiological association with AD while also inducing eczematous dysbiosis.

PMID:36608129 | DOI:10.1126/sciadv.ade8898

J Craniofac Surg. 2023 Jan-Feb 01;34(1):288-290. doi: 10.1097/SCS.0000000000008878. Epub 2022 Aug 17.

ABSTRACT

Postoperative monitoring plays an important role in achieving success in microvascular free tissue transfer. A systematic review was designed to evaluate the clinical outcomes of microdialysis in flap monitoring and a meta-analysis was conducted for diagnostic accuracies. The search terms “microdialysis” and “flap” were used in a PubMed and Scopus search, resulting in 60 and 78 results, respectively. Among 78 titles, 15 articles were excluded. Among 63 abstracts, 43 abstracts were excluded. From 20 full texts, 7 articles were excluded because they did not have sufficient content (ie, the statistical values in question). A systematic review was conducted of the final 13 articles. The overall sensitivity was 97.24% [95% confidence interval (CI)=93.67%-99.10%]. Eleven of the 13 studies showed 100% sensitivity and 2 studies had 2 and 3 false negative results, resulting in sensitivity values of 85.8% and 95.3%. Specificity ranged from 91.89% to 100%, and the overall value was 98.15% (95% CI=96.80%-99.04%). The positive predictive value ranged from 84.62% to 100%, with an overall value of 93.62% (95% CI=89.33%-96.26%). The negative predictive value ranged from 94.44% to 100%, with an overall value of 99.22% (95% CI=98.17%-99.67%). The overall flap success rate (survival rate) was 93.7% (786/839). The lowest flap survival rate was 86.7% and the highest was 100%. Microdialysis provides excellent diagnostic accuracy and enables the early detection of ischemia in postoperative flap monitoring. Although microdialysis is not the most popular choice among surgeons, it should be considered adjacent to conventional clinical monitoring. Cost-effectiveness, availability, and ease of application remain hurdles.

PMID:36608107 | DOI:10.1097/SCS.0000000000008878

J Craniofac Surg. 2023 Jan-Feb 01;34(1):267-271. doi: 10.1097/SCS.0000000000008864. Epub 2022 Aug 2.

ABSTRACT

This study aimed to determine the mean values of the nasal anthropometric measurements through 2-dimensional photogrammetry in for rhinoplasty patients. The study group included 72 healthy individuals, 36 men, and 36 women. The patients were aged 18 to 42 years. All patients had undergone primary rhinoplasty in our clinic between 2013 and 2020. Seven landmarks were identified from the preoperative photographs taken with the patient’s head in neutral position in the frontal and lateral planes. Five distances (total nasal length, nasal bridge length, morphological nose width, alar length, and nasal tip protrusion) and 2 angles (nasofrontal and nasolabial) measurements were calculated. We noted a statistically significant difference between the male and female sexes in terms of total nasal length and morphological nose width (P<0.05). The results were compared with the nasal anthropometric measurements reported in the literature for the Turkish population as well as other ethnic groups. We believe results of this study may facilitate preoperative planning in Turkish patients who request rhinoplasty and improve the success rate of the surgery.

PMID:36608106 | DOI:10.1097/SCS.0000000000008864

Am J Ther. 2023 Jan-Feb 01;30(1):e36-e55. doi: 10.1097/MJT.0000000000001584. Epub 2022 Dec 20.

ABSTRACT

BACKGROUND: We present a systematic review and network meta-analysis (NMA) that is the precursor underpinning the Bayesian analyses that adjust for publication bias, presented in the same edition in AJT. The review assesses optimal cytoreduction for women undergoing primary advanced epithelial ovarian cancer (EOC) surgery.

AREAS OF UNCERTAINTY: To assess the impact of residual disease (RD) after primary debulking surgery in women with advanced EOC. This review explores the impact of leaving varying levels of primary debulking surgery.

DATA SOURCES: We conducted a systematic review and random-effects NMA for overall survival (OS) to incorporate direct and indirect estimates of RD thresholds, including concurrent comparative, retrospective studies of ≥100 adult women (18+ years) with surgically staged advanced EOC (FIGO stage III/IV) who had confirmed histological diagnoses of ovarian cancer. Pairwise meta-analyses of all directly compared RD thresholds was previously performed before conducting this NMA, and the statistical heterogeneity of studies within each comparison was evaluated using recommended methods.

THERAPEUTIC ADVANCES: Twenty-five studies (n = 20,927) were included. Analyses demonstrated the prognostic importance of complete cytoreduction to no macroscopic residual disease (NMRD), with a hazard ratio for OS of 2.0 (95% confidence interval, 1.8-2.2) for <1 cm RD threshold versus NMRD. NMRD was associated with prolonged survival across all RD thresholds. Leaving NMRD was predicted to provide longest survival (probability of being best = 99%). The results were robust to sensitivity analysis including only those studies that adjusted for extent of disease at primary surgery (hazard ratio 2.3, 95% confidence interval, 1.9-2.6). The overall certainty of evidence was moderate and statistical adjustment of effect estimates in included studies minimized bias.

CONCLUSIONS: The results confirm a strong association between complete cytoreduction to NMRD and improved OS. The NMA approach forms part of the methods guidance underpinning policy making in many jurisdictions. Our analyses present an extension to the previous work in this area.

PMID:36608071 | DOI:10.1097/MJT.0000000000001584

Am J Ther. 2023 Jan-Feb 01;30(1):e1-e9. doi: 10.1097/MJT.0000000000001573. Epub 2022 Nov 11.

ABSTRACT

BACKGROUND: Emerging evidence suggests low-dose buprenorphine (LDB) induction can expand opportunities for buprenorphine induction in patients who are taking taking methadone, short-acting opioid agonists, or who have anxiety about opioid withdrawal.

STUDY QUESTION: How is a rapid LDB protocol using transdermal buprenorphine tolerated in the hospital?

STUDY DESIGN: A prospective study of 20 patient encounters (n = 20 patients) with traditional buprenorphine induction before implementation of study protocol (control group) and 37 patient encounters (n = 34 patients) with LDB induction protocol (pilot group). Summary statistics were used to describe demographics, clinical opioid withdrawal scale and pain scores within 24 hours preprotocol and within 24 hours postprotocol initiation, hospital length of stay after protocol initiation, receipt of a buprenorphine prescription at discharge, and prescription activity at 30 days. T test and chi-square tests were used to analyze comparisons. A subset of pilot group patients completed a survey about their experience.

RESULTS: There were no statistically significant differences in pain and clinical opioid withdrawal scale scores between the pilot and control groups. There were 5 instances of precipitated withdrawal in the pilot group. There was no statistically significant difference in mean discharge time after protocol initiation between the pilot and control groups (P = 0.60). Most patients surveyed described a positive experience with LDB induction.

CONCLUSION: Hospitalization is a critical time to initiate buprenorphine for patients with opioid use disorder. Our data adds to the growing evidence that LDB induction is feasible for patients taking methadone and short-acting opioid agonists, and that a more rapid induction protocol is generally well-tolerated by patients although precipitated withdrawal is a risk. Finally, our rapid induction protocol did not seem to increase hospital length of stay compared with traditional induction.

PMID:36608069 | DOI:10.1097/MJT.0000000000001573

Am J Ther. 2022 Nov-Dec 01;29(6):e616-e624. doi: 10.1097/MJT.0000000000001558. Epub 2022 Aug 23.

ABSTRACT

BACKGROUND: Progressive chronic diseases presume a complex treatment plan that depends on the number of symptoms, their severity, and comorbidities. Drug management is an essential responsibility of the family caregiver of a palliative care patient, but has received limited attention in field research.

STUDY QUESTIONS: The aim of this study is to identify the complexity of the therapeutic plan followed at home by cancer or noncancer patients needing palliative care, and to assess its impact on the burden of the family caregivers.

STUDY DESIGN: This observational study was conducted at patient’s admission in a palliative care department. The study involved cancer and noncancer patients and their primary family caregivers. To measure the care burden, the Burden Scale for Family Caregiver was used and for the complexity of the therapeutic plan, the Medication Regime Complexity Index.

MEASURES AND OUTCOMES: To measure the care burden, the Burden Scale for Family Caregiver was used and for the complexity of the therapeutic plan, the Medication Regime Complexity Index.

RESULTS: One hundred and forty patients were enrolled with their family caregivers: patients with nononcological pathologies (n = 63) and patients with cancer (n = 77). Caregiver’s burden score is statistically significantly correlated with the complexity of the medical plan in both groups (P = 0.32 and P = 0.012 respectively). The average family caregiver’s burden was significantly higher in the nononcological group (45 ± 14.45 vs. 36.52 ± 15.05; P = 0.001). The number of medications that family caregivers administer daily for patients without cancer is higher than in the other subset (8.25 ± 4.94 vs. 5.89 ± 4.93; P = 0.004). Opioids were more frequently used for pain control in cancer patients (5 vs. 72; P = 0.0001).

CONCLUSIONS: The caregiver’s burden is high for nononcological patients. The complexity of the treatment plan (number of drugs and frequency of administration) is significantly correlated with the care burden. Further studies are needed to understand which interventions targeted on family caregivers will minimize the burden of care.

PMID:36608062 | DOI:10.1097/MJT.0000000000001558

PLoS One. 2023 Jan 6;18(1):e0280057. doi: 10.1371/journal.pone.0280057. eCollection 2023.

ABSTRACT

Scientific literature is giving greater importance to dynamic balance in fall prevention. Recently, the validity and reliability of the most employed functional tests for dynamic balance assessment has been investigated. Although these functional tests are practical and require minimal equipment, they are inherently subjective, as most do not use instrumented measurement data in the scoring process. Therefore, this study aimed to assess the validity and reliability of an instrumented unstable board for dynamic balance objective assessment in young adults through double-leg standing trials. A test-retest design was outlined with the unstable board positioned over a force platform to collect objective Center of Pressure (CoP) related and kinematic parameters. Fifteen young adults participated in two evaluation sessions (7-day apart) that comprised ten trials per two dynamic conditions (anterior-posterior and medio-lateral oscillations) aiming to maintain the board parallel to the ground. Pearson’s correlation coefficient (r) was employed to assess the validity of the kinematic parameters with those derived from the CoP. The test-retest reliability was investigated through Intraclass Correlation Coefficient (ICC), Standard Error of the measurement, Minimal Detectable Change, and Bland-Altman plots. Statistically significant correlations between the CoP and kinematic parameters were found, with r values ranging from 0.66 to 0.95. Good to excellent intrasession (0.89≤ICCs≤0.95) and intersession (0.66≤ICCs≤0.95) ICCs were found for the kinematics parameters. The Bland-Altman plots showed no significant systematic bias. The kinematics parameters derived from the unstable board resulted valid and reliable. The small size of the board makes it a suitable tool for the on-site dynamic balance assessment and a complement of computerized dynamic posturography.

PMID:36608060 | DOI:10.1371/journal.pone.0280057