Category: Statistics

Clin Infect Dis. 2021 Aug 11:ciab677. doi: 10.1093/cid/ciab677. Online ahead of print.

ABSTRACT

Clinical trials of severe sepsis that target crude (total) mortality as an end point do not have sufficient power to detect differences in mortality due to the intervention. We aim to discuss the importance of including the subcomponents of crude mortality in study design; estimate how sample size requirements change based on the proportion of attributable mortality; and how minor changes from predicted outcomes can affect results. We derived statistical curves to illustrate our points.

PMID:34379735 | DOI:10.1093/cid/ciab677

PLoS One. 2021 Aug 11;16(8):e0255915. doi: 10.1371/journal.pone.0255915. eCollection 2021.

ABSTRACT

Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing TCGA-gastric adenocarcinoma dataset. Small leucine-rich proteoglycans, asporin (ASPN) and decorin (DCN), play overlapping roles in development and diseases; however, the mechanisms underlying their interplay remain elusive. Here, we investigated the complex interplay of asporin, decorin and their interaction with TGFβ in GC tumor and corresponding normal tissues. The mRNA levels, protein expressions and cellular localizations of ASPN and DCN were analyzed using real-time PCR, western blot and immunohistochemistry, respectively. The protein-protein interaction was predicted by in-silico interaction analysis and validated by co-immunoprecipitation assay. The correlations between ASPN and EMT proteins, VEGF and collagen were achieved using western blot analysis. A significant increase in expression of ASPN in tumor tissue vs. normal tissue was observed in both TCGA and our patient cohort. DCN, an effective inhibitor of the TGFβ pathway, was negatively correlated with stages of GC. Co-immunoprecipitation demonstrated that DCN binds with TGFβ, in normal gastric epithelium, whereas in GC, ASPN preferentially binds TGFβ. Possible activation of the canonical TGFβ pathway by phosphorylation of SMAD2 in tumor tissues suggests its role as an intracellular tumor promoter. Furthermore, tissues expressing ASPN showed unregulated EMT signalling. Our study uncovers ASPN as a GC-promoting gene and DCN as tumor suppressor, suggesting that ASPN can act as a prognostic marker in GC. For the first time, we describe the physical interaction of TGFβ with ASPN in GC and DCN with TGFβ in GC and normal gastric epithelium respectively. This study suggests that prevention of ASPN-TGFβ interaction or overexpression of DCN could serve as promising therapeutic strategies for GC patients.

PMID:34379688 | DOI:10.1371/journal.pone.0255915

PLoS One. 2021 Aug 11;16(8):e0255917. doi: 10.1371/journal.pone.0255917. eCollection 2021.

ABSTRACT

BACKGROUND: Pulmonary tumor embolism (PTE) is difficult to detect before death, and it is unclear whether the discrepancy between antemortem clinical and postmortem diagnosis improves with the advance of the diagnostic technologies. In this study we determined the incidence of PTE and analyzed the discrepancy between antemortem clinical and postmortem diagnosis.

METHODS: We performed a retrospective autopsy study on patients with the history of malignant solid tumors from 1990 to 2020 and reviewed all the slides of the patients with PTE. We also analyzed the discrepancies between antemortem clinical and postmortem diagnosis in 1999, 2009 and 2019 by using the Goldman criteria. Goldman category major 1 refers to cases in which an autopsy diagnosis was the direct cause of death and was not recognized clinically, but if it had been recognized, it may have changed treatment or prolonged survival.

RESULTS: We found 20 (3%) cases with PTE out of the 658 autopsy cases with solid malignancies. Out of these 20 cases, urothelial carcinoma (30%, 6/20) and invasive ductal carcinoma of the breast (4/20, 20%) were the most common primary malignancies. Seven patients with shortness of breath died within 3-17 days (average 8.4±2.2 days) after onset of the symptoms. Pulmonary embolism was clinically suspected in seven out of twenty (35%, 7/20) patients before death, but only two patients (10, 2/20) were diagnosed by imaging studies before death. The rate of Goldman category major 1 was 13.2% (10/76) in 1999, 7.3% (4/55) in 2009 and 6.9% (8/116) in 2019. Although the rate of Goldman category major 1 appeared decreasing, the difference was not statistically significant. The autopsy rate was significantly higher in 2019 (8.4%, 116/1386) than in 2009 (4.4%, 55/1240).

CONCLUSIONS: The incidence of PTE is uncommon. Despite the advances of the radiological techniques, radiological imaging studies did not detect the majority of PTEs. The discrepancy between the antemortem clinical and the postmortem diagnosis has not improved significantly over the past 30 years, emphasizing the value of autopsy.

PMID:34379693 | DOI:10.1371/journal.pone.0255917

PLoS One. 2021 Aug 11;16(8):e0256034. doi: 10.1371/journal.pone.0256034. eCollection 2021.

ABSTRACT

Identifying coordinated activity within complex systems is essential to linking their structure and function. We study collective activity in networks of pulse-coupled oscillators that have variable network connectivity and integrate-and-fire dynamics. Starting from random initial conditions, we see the emergence of three broad classes of behaviors that differ in their collective spiking statistics. In the first class (“temporally-irregular”), all nodes have variable inter-spike intervals, and the resulting firing patterns are irregular. In the second (“temporally-regular”), the network generates a coherent, repeating pattern of activity in which all nodes fire with the same constant inter-spike interval. In the third (“chimeric”), subgroups of coherently-firing nodes coexist with temporally-irregular nodes. Chimera states have previously been observed in networks of oscillators; here, we find that the notions of temporally-regular and chimeric states encompass a much richer set of dynamical patterns than has yet been described. We also find that degree heterogeneity and connection density have a strong effect on the resulting state: in binomial random networks, high degree variance and intermediate connection density tend to produce temporally-irregular dynamics, while low degree variance and high connection density tend to produce temporally-regular dynamics. Chimera states arise with more frequency in networks with intermediate degree variance and either high or low connection densities. Finally, we demonstrate that a normalized compression distance, computed via the Lempel-Ziv complexity of nodal spike trains, can be used to distinguish these three classes of behavior even when the phase relationship between nodes is arbitrary.

PMID:34379694 | DOI:10.1371/journal.pone.0256034

PLoS One. 2021 Aug 11;16(8):e0255801. doi: 10.1371/journal.pone.0255801. eCollection 2021.

ABSTRACT

Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.

PMID:34379647 | DOI:10.1371/journal.pone.0255801

PLoS One. 2021 Aug 11;16(8):e0255910. doi: 10.1371/journal.pone.0255910. eCollection 2021.

ABSTRACT

BACKGROUND: Previous studies have found that healthcare-associated bacteremia (HAB) by Aeromonas species is associated with mortality. However, there is limited data on this outcome in patients with hematologic malignancies. This study aimed to identify the clinical features of patients with malignant hematologic diseases diagnosed with Aeromonas sobria bacteremia and to evaluate whether the type of bacteremia, community-acquired bacteremia (CAB) or HAB, is associated with mortality.

METHODS: We retrospectively reviewed the clinical records of pediatric and adult patients between January 2000 and December 2017. Clinical characteristics were compared between CAB and HAB. Additionally, we stratified based on age group. Survival outcomes were assessed with Kaplan-Meier curves and a multivariate Cox regression analysis.

RESULTS: A total of 37 patients (median age 24 years) were identified; 23 (62%) had HAB and 14 (38%) had CAB. Overall, the most common presenting symptom was abdominal pain (41%). Acute lymphoblastic leukemia (n = 12/15, 80%) and acute myeloid leukemia (n = 8/22, 36%) were the primary hematologic malignancies in pediatric and adult patients, respectively. CAB patients had worse overall survival (OS) rates at 30 days in all (43% versus HAB 91%, p = 0.006) and adult patients (30% versus HAB 92%, p = 0.002). Cox regression analysis found that quick Sequential Organ Failure Assessment and CAB were statistically significant factors associated with mortality. Low antimicrobial-resistant was noted, except for ciprofloxacin (n = 5/37, 14%).

CONCLUSION: Our study found a worse OS among patients with hematologic malignancies and CAB by Aeromonas sobria. Our results suggest that patients with CAB present with a worse disease severity. These findings should aid clinicians to determine the survival prognosis in this population.

PMID:34379680 | DOI:10.1371/journal.pone.0255910

Stat Appl Genet Mol Biol. 2021 Aug 9. doi: 10.1515/sagmb-2021-0004. Online ahead of print.

ABSTRACT

Statistical methods that allow for cell type specific DNA methylation (DNAm) analyses based on bulk-tissue methylation data have great potential to improve our understanding of human disease and have created unprecedented opportunities for new insights using the wealth of publicly available bulk-tissue methylation data. These methodologies involve incorporating interaction terms formed between the phenotypes/exposures of interest and proportions of the cell types underlying the bulk-tissue sample used for DNAm profiling. Despite growing interest in such “interaction-based” methods, there has been no comprehensive assessment how variability in the cellular landscape across study samples affects their performance. To answer this question, we used numerous publicly available whole-blood DNAm data sets along with extensive simulation studies and evaluated the performance of interaction-based approaches in detecting cell-specific methylation effects. Our results show that low cell proportion variability results in large estimation error and low statistical power for detecting cell-specific effects of DNAm. Further, we identified that many studies targeting methylation profiling in whole-blood may be at risk to be underpowered due to low variability in the cellular landscape across study samples. Finally, we discuss guidelines for researchers seeking to conduct studies utilizing interaction-based approaches to help ensure that their studies are adequately powered.

PMID:34378875 | DOI:10.1515/sagmb-2021-0004

Cancer Biol Med. 2021 Aug 11:j.issn.2095-3941.2021.0037. doi: 10.20892/j.issn.2095-3941.2021.0037. Online ahead of print.

ABSTRACT

OBJECTIVE: Distinguishing immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) from the AEs caused by chemotherapy, targeted therapy, or infection is highly difficult. This study offers new insights into evaluating the diagnosis, differential diagnostic, and prognostic value of ferritin for irAEs induced by ICIs.

METHODS: From December 1, 2018, to April 1, 2019, we examined 318 patients with malignant tumors who received serum ferritin monitoring. The cohort comprised 231 patients treated with PD-1 inhibitor or combination with chemotherapy, and 87 patients treated with chemotherapy. Of the 231 patients, 90 had irAEs (irAE group), 70 had non-irAEs (non-irAE group), 67 had no AEs (no irAE-non irAE group), and 4 had unclassified AEs. In the 87 patients, 60 had AEs (AE group), and 27 had no AEs (no AE group). Statistical analyses were conducted with nonparametric Mann-Whitney tests.

RESULTS: At the onset of AEs in the irAE group, ferritin (normal range, 35-150 μg/L) rose to a median of 927 μg/L (range, 117-17,825 μg/L) from 86 μg/L at baseline (range, 29-421 μg/L) (P < 0.001). Ferritin levels at the onset of AEs in the irAE group were significantly higher than those in the non-irAE group (median, 81 μg/L; range, 32-478 μg/L) (P < 0.001) and the AE group (median, 103 μg/L; range, 23-712 μg/L) (P < 0.001). After treatment in the irAE group, ferritin continuously decreased to a normal range in recovered patients, showed no significant changes in stable patients, and continued to rise in patients who died.

CONCLUSIONS: Ferritin can be used as a diagnostic, differential diagnostic, and prognostic marker for irAEs in patients treated with ICIs.

PMID:34378879 | DOI:10.20892/j.issn.2095-3941.2021.0037

Clin Implant Dent Relat Res. 2021 Aug 11. doi: 10.1111/cid.13039. Online ahead of print.

ABSTRACT

BACKGROUND: In immediately loaded implants within 72 h after the implant placement in the unilaterally and partially edentulous ridge, primary stability is considered critical, which can be influenced by the design of the implant fixture.

PURPOSE: To determine the outcomes at 1 year after the immediate loading of multiunit fixed partial prostheses over either tapered implants (TIs) or straight implants (SIs) in the posterior region.

MATERIALS AND METHODS: Forty-eight patients (24 patients, 52 implants in TI group; 24 patients, 50 implants in SI group) were included for the study. Except for the one SI group patient whose two implants showed the insertion torque less than 30 Ncm, provisional prostheses designed and fabricated from intraoral scan data obtained immediately after implant surgery were delivered to rest of the 47 subjects at 3-7 days. After a year, the survival rate was estimated by intention-to-treat (ITT) and per-protocol (PP) analyses, and marginal bone loss (MBL) and implant stability were also analyzed statistically (p < 0.05).

RESULTS: Survival rate at implant level in TI group was 96.2%, and that of SI group in the ITT analysis was 86.0%. Intergroup difference, however, was not statistically significant (p > 0.05). Insertion torque was significantly higher in TI group than SI group (47.12 ± 6.37 Ncm vs. 41.60 ± 9.77 Ncm; p < 0.05). MBLs of both groups were less than 0.1 mm at 1-year follow-up and was similar between two groups (p > 0.05).

CONCLUSIONS: Immediate loading of fixed partial prostheses after TI and SI placement showed reliable outcomes in the partially edentulous posterior ridge. In terms of the initial mechanical stability, the performance was superior for TIs than for SIs.

PMID:34378853 | DOI:10.1111/cid.13039

Ther Apher Dial. 2021 Aug 11. doi: 10.1111/1744-9987.13722. Online ahead of print.

ABSTRACT

Long term dialysis involves a chronic inflammatory state and produces a high prevalence of vitamin D deficiency. A clinical trial was conducted in hemodialysis with serum 25-hydroxyvitamin D (25[OH]D) level < 30 ng/mL. The conventional-group (N = 35) and the high-dose group (N = 35) were treated with ergocalciferol according to the K/DOQI guidelines and double dosage of ergocalciferol from the recommendation for 8 weeks, respectively. The main outcomes were measured by serum 25[OH]D and interleukin-6 (IL-6). At the end of 8 weeks, a statistically significantly greater increase was observed of mean serum 25[OH]D levels and decrease of mean PTH levels in the high-dose group compared with the conventional-dose group. The high dose group had higher achievement of vitamin D sufficiency than the conventional-dose group (97.4% vs. 76.4%, P = 0.012). No significance difference was found in mean changes of serum IL-6 level in the both groups, except subgroup patients with vitamin D deficiency or serum 25[OH]D < 20 ng/mL, high dose treatment suppressed serum IL-6 level (-2.67 pg/mL [IQR -6.56 to -0.17], P = 0.039). No differences were observed between the two groups in adverse events. Oral high-dose ergocalciferol supplementation has achieved higher vitamin D sufficiency than standard dose in ESRD patients on dialysis.

PMID:34378863 | DOI:10.1111/1744-9987.13722