Tag: statistics

Metabolomics. 2022 Nov 13;18(11):92. doi: 10.1007/s11306-022-01949-w.

ABSTRACT

INTRODUCTION: PKCδ is ubiquitously expressed in mammalian cells and its dysregulation plays a key role in the onset of several incurable diseases and metabolic disorders. However, much remains unknown about the metabolic pathways and disturbances induced by PKC deficiency, as well as the metabolic mechanisms involved.

OBJECTIVES: This study aims to use metabolomics to further characterize the function of PKC from a metabolomics standpoint, by comparing the full serum metabolic profiles of PKC deficient mice to those of wild-type mice.

METHODS: The serum metabolomes of PKCδ knock-out mice were compared to that of a wild-type strain using a GCxGC-TOFMS metabolomics research approach and various univariate and multivariate statistical analyses.

RESULTS: Thirty-seven serum metabolite markers best describing the difference between PKCδ knock-out and wild-type mice were identified based on a PCA power value > 0.9, a t-test p-value < 0.05, or an effect size > 1. XERp prediction was also done to accurately select the metabolite markers within the 2 sample groups. Of the metabolite markers identified, 78.4% (29/37) were elevated and 48.65% of these markers were fatty acids (18/37). It is clear that a total loss of PKCδ functionality results in an inhibition of glycolysis, the TCA cycle, and steroid synthesis, accompanied by upregulation of the pentose phosphate pathway, fatty acids oxidation, cholesterol transport/storage, single carbon and sulphur-containing amino acid synthesis, branched-chain amino acids (BCAA), ketogenesis, and an increased cell signalling via N-acetylglucosamine.

CONCLUSION: The charaterization of the dysregulated serum metabolites in this study, may represent an additional tool for the early detection and screening of PKCδ-deficiencies or abnormalities.

PMID:36371785 | DOI:10.1007/s11306-022-01949-w

Hum Brain Mapp. 2022 Nov 13. doi: 10.1002/hbm.26112. Online ahead of print.

ABSTRACT

In this manuscript, we consider the problem of relating functional connectivity measurements viewed as statistical distributions to outcomes. We demonstrate the utility of using the distribution of connectivity on a study of resting-state functional magnetic resonance imaging association with an intervention. The method uses the estimated density of connectivity between nodes of interest as a functional covariate. Moreover, we demonstrate the utility of the procedure in an instance where connectivity is naturally considered an outcome by reversing the predictor/response relationship using case/control methodology. The method utilizes the density quantile, the density evaluated at empirical quantiles, instead of the empirical density directly. This improved the performance of the method by highlighting tail behavior, though we emphasize that by being flexible and non-parametric, the technique can detect effects related to the central portion of the density. To demonstrate the method in an application, we consider 47 primary progressive aphasia patients with various levels of language abilities. These patients were randomly assigned to two treatment arms, transcranial direct-current stimulation and language therapy versus sham (language therapy only), in a clinical trial. We use the method to analyze the effect of direct stimulation on functional connectivity. As such, we estimate the density of correlations among the regions of interest and study the difference in the density post-intervention between treatment arms. We discover that it is the tail of the density, rather than the mean or lower order moments of the distribution, that demonstrates a significant impact in the classification. The new approach has several benefits. Among them, it drastically reduces the number of multiple comparisons compared with edge-wise analysis. In addition, it allows for the investigation of the impact of functional connectivity on the outcomes where the connectivity is not geometrically localized.

PMID:36371779 | DOI:10.1002/hbm.26112

Eur Spine J. 2022 Nov 13. doi: 10.1007/s00586-022-07451-0. Online ahead of print.

ABSTRACT

PURPOSE: The goal of this study was to provide recent data on incidence of spinal cord injuries (SCI) in Germany.

METHODS: The source of information was data collected via the mandatory submission of ICD-10 GM Codes by German public hospitals after patient discharge. Data from 2013 to 2020 were retrieved from the databases of the Federal Bureau of Statistics. ICD-10 Codes for acute SCI were identified. Statistical analysis was performed using Jamovi and Excel.

RESULTS: A total of 10,360 patients were reported, of whom 58.7% suffered from a cervical, 30.8% a thoracic and 10.4% a lumbar lesion. Two peaks in incidence were observed at approximately 30 and 70 years old. A population-size-adjusted overall incidence of 15.73 (SD 0.77) per million per year was calculated. We calculated the incidences in several subpopulations and discovered significantly higher incidences among males and among those over the age of 60. We discovered that differences in age groups mainly concerned injuries of the upper spine, with the incidence in the lumbar spine being similar among age groups. In addition, we found that while the probability of suffering from SCI increases with age, the relative risk of suffering from a complete injury decreases.

CONCLUSIONS: This study closes a long-lasting gap in epidemiological data regarding SCI in Germany, specifically by updating the incidence rates. We found that incidence depends on age, gender and type of lesion. We also provide some new angles for future research, especially considering the relative reduction in complete injuries among the elderly.

PMID:36371751 | DOI:10.1007/s00586-022-07451-0

Int J Comput Assist Radiol Surg. 2022 Nov 13. doi: 10.1007/s11548-022-02781-2. Online ahead of print.

ABSTRACT

PURPOSE: Ki67 is a protein associated with tumor proliferation and metastasis in breast cancer and acts as an essential prognostic factor. Clinical work requires recognizing tumor regions on Ki67-stained whole-slide images (WSIs) before quantitation. Deep learning has the potential to provide assistance but largely relies on massive annotations and consumes a huge amount of time and energy. Hence, a novel tumor region recognition approach is proposed for more precise Ki67 quantification.

METHODS: An unsupervised domain adaptive method is proposed, which combines adversarial and self-training. The model trained on labeled hematoxylin and eosin (H&E) data and unlabeled Ki67 data can recognize tumor regions in Ki67 WSIs. Based on the UDA method, a Ki67 automated assisted quantification system is developed, which contains foreground segmentation, tumor region recognition, cell counting, and WSI-level score calculation.

RESULTS: The proposed UDA method achieves high performance in tumor region recognition and Ki67 quantification. The AUC reached 0.9915, 0.9352, and 0.9689 on the validation set and internal and external test sets, respectively, substantially exceeding baseline (0.9334, 0.9167, 0.9408) and rivaling the fully supervised method (0.9950, 0.9284, 0.9652). The evaluation of automated quantification on 148 WSIs illustrated statistical agreement with pathological reports.

CONCLUSION: The model trained by the proposed method is capable of accurately recognizing Ki67 tumor regions. The proposed UDA method can be readily extended to other types of immunohistochemical staining images. The results of automated assisted quantification are accurate and interpretable to provide assistance to both junior and senior pathologists in their interpretation.

PMID:36371746 | DOI:10.1007/s11548-022-02781-2

J Bone Miner Metab. 2022 Nov 13. doi: 10.1007/s00774-022-01378-8. Online ahead of print.

ABSTRACT

INTRODUCTION: Incomplete atypical femoral fractures (iAFF) may occur with prolonged bisphosphonate usage. Factors influencing iAFF healing and progression are not well understood. This study of conservatively managed iAFF assessed factors influencing iAFF healing and progression including the effects of bisphosphonates and teriparatide use.

MATERIALS AND METHODS: Single-center retrospective observational study of 69 consecutive patients with 78 radiographically confirmed iAFF from 2002 to 2017. Serial radiographs assessed for focal cortical thickening, dreaded black line (DBL) and complete fracture. Chief outcome measures were DBL healing and complete fracture.

RESULTS: DBL had a significant association (p < 0.05) with fracture progression by multivariable logistic regression (55.8% versus 25.7%, odds ratio [OR] 26.57 (95% CI 1.40-504.78)) and shorter fracture-free survival (mean 3.21 versus 6.27 years). Presence of symptoms was associated with shorter fracture-free survival (mean 2.68 versus 5.98 years). Discontinuing bisphosphonates had significant associations (p < 0.001) by multivariable logistic regression with decreased fracture rate (11.6% versus 92.0%; OR 0.00, 95% CI 0.00-0.08) and longer fracture-free survival (mean 7.52 versus 1.99 years). DBL healing occurred in 36.4%, only when bisphosphonates were discontinued. Age, sex, race, fracture site, glucocorticoid use, teriparatide supplementation and duration of bisphosphonate use showed no statistically significant effect although teriparatide use appeared to improve DBL healing (50% versus 17.9%, p = 0.188).

CONCLUSIONS: In conservatively managed iAFF, DBL healing occurred in 36.4% if bisphosphonates were discontinued. Bisphosphonates and DBL were significantly associated with fracture progression and together with symptoms with fracture survival.

PMID:36371726 | DOI:10.1007/s00774-022-01378-8

Med Phys. 2022 Nov 13. doi: 10.1002/mp.16059. Online ahead of print.

ABSTRACT

Resistance of high grade tumors to treatment involves cancer stem cell features, deregulated cell division, acceleration of genomic errors, and emergence of cellular variants that rely upon diverse signaling pathways. This heterogeneous tumor landscape limits the utility of the focal sampling provided by invasive biopsy when designing strategies for targeted therapies. In this roadmap review paper, we propose and develop methods for enabling mapping of cellular and molecular features in vivo to inform and optimize cancer treatment strategies in the brain. This approach leverages 1) the spatial and temporal advantages of in vivo imaging compared with surgical biopsy, 2) the rapid expansion of meaningful anatomical and functional MR signals, 3) widespread access to cellular and molecular information enabled by next generation sequencing, and 4) the enhanced accuracy and computational efficiency of deep learning techniques. As multiple cellular variants may be present within volumes below the resolution of imaging, we describe a mapping process to decode micro- and even nano-scale properties from the macro-scale data by simultaneously utilizing complimentary multiparametric image signals acquired in routine clinical practice. We outline design protocols for future research efforts that marry revolutionary bioinformation technologies, growing access to increased computational capability, and powerful statistical classification techniques to guide rational treatment selection. This article is protected by copyright. All rights reserved.

PMID:36371678 | DOI:10.1002/mp.16059

J Pathol. 2022 Nov 13. doi: 10.1002/path.6028. Online ahead of print.

ABSTRACT

Esophageal basaloid squamous cell carcinoma (bSCC) is a subtype of squamous cell carcinoma (SCC) with different behavior and poor prognosis. Exploring bSCC’s molecular characteristics and treatment strategies are of great clinical significance. We performed multi-omics analysis of paired bSCC and common SCC (cSCC) using Whole Exome Sequencing and a NanoString nCounter gene expression panel. Immunohistochemistry was used for verification of candidate biomarkers. Different treatment response was analyzed on both patients receiving neoadjuvant treatment and on late-stage patients. The common genetically-clonal origin of bSCC and cSCC was confirmed. No significant differences between their genetic alterations or mutation spectra were observed. Mutation signature 15 (associated with defective DNA damage repair) was less prominent, and TMB was lower in bSCC. bSCC with RNA expression pattern resembling cSCC had better survival than other bSCC. Moreover, bSCC showed significant upregulation of expression of genes associated with angiogenesis response, basement membranes, epithelial-mesenchymal transition, and downregulation of KRT14 (squamous differentiation) and of CCL21 (associated with immune response). Immunohistochemistry for SFRP1 was shown to be highly sensitive and specific for bSCC diagnosis (p<0.001). In addition, bSCC receiving neoadjuvant immuno-chemotherapy had worse pathological response than neoadjuvant chemotherapy (but without statistical significance), even in bSCC positive for PD-L1. Our results demonstrated the molecular characteristics of esophageal bSCC as a subtype with distinct RNA expression pattern and immune characteristics, but no specific genetic mutations. We provided a useful biomarker, SFRP1, for diagnosis. With outcome analysis for 6 bSCCs with neoadjuvant immunotherapy treatment and 4 late-stage bSCCs with immunotherapy, we found that immunotherapy may not be an effective treatment option for most bSCC. This may also provide a clue for the same subtypes of lung and head and neck cancer. Our study highlighted the heterogeneity among bSCC patients, and might explained the conflicting results of bSCC outcomes in existing studies. This article is protected by copyright. All rights reserved.

PMID:36371676 | DOI:10.1002/path.6028

Eur J Neurol. 2022 Nov 12. doi: 10.1111/ene.15632. Online ahead of print.

ABSTRACT

BACKGROUND: Approximately 30% of epilepsy patients develop a drug-refractory epilepsy (DRE), i.e., seizures cannot be controlled with antiepileptic drugs. Surgery has been evaluated as an effective, but costly form of treatment. The aim of this systematic review is to synthesize the available evidence on the cost-effectiveness of surgical treatment compared to medical treatment for these patients.

METHODS: A systematic literature search was performed in MEDLINE, EMBASE, PsycINFO, Cochrane Library, and NHS EED until September 2022. Title, abstract, and full-text screening were conducted by two researchers. We included original studies published in English or German analyzing the cost-effectiveness of surgical compared to medical treatment. Study characteristics, effectiveness measures, costs, and incremental cost-effectiveness ratios (ICERs) were extracted. The quality of studies was assessed using the Drummond checklist.

RESULTS: 14 studies were included. Most studies evaluated surgery as cost-effective: The ICER per patient seizure free ranged from dominant to purchasing power parity US dollars (PPP-USD) 479,275. The ICER per 1% seizure reduction ranged from PPP-USD 227 to PPP-USD 342. The ICER per year without seizures was PPP-USD 4,202 and the ICER per QALY ranged from dominant to PPP-USD 90,874. The studies varied greatly in their methodology and time horizon.

CONCLUSION: Surgical treatment is cost-effective compared to medical treatment, especially when a lifetime horizon is adopted. We conclude that all disease-specific costs should be considered over a long period when assessing the cost-effectiveness of epilepsy treatment. From an economic perspective, efforts should be made to improve access to surgical treatment for patients with DRE.

PMID:36371643 | DOI:10.1111/ene.15632

JPEN J Parenter Enteral Nutr. 2022 Nov 12. doi: 10.1002/jpen.2463. Online ahead of print.

ABSTRACT

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM)-defined malnutrition has been associated with cancer mortality, while the effect is limited and inconsistent. We performed this meta-analysis aiming to assess this relationship in patients with cancer.

METHODS: We systematically searched Embase, PubMed, Web of Science, Cochrane, CINAHL, CNKI, Wanfang and VIP databases from 1 January 2019 to 1 July 2022. Studies evaluating the prognostic effect of GLIM-defined malnutrition on cancer survival were included. A fix-effect model was fitted to estimate the combined hazard ratio (HR) with 95% confidence interval (CI). Heterogeneity of studies was analyzed using the I² statistic. Quality assessment were performed using the Newcastle-Ottawa Scale (NOS) and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool.

RESULTS: The search strategy identified 4378 articles in all databases combined. Nine studies (8829 patients) met the inclusion criteria were included for quantitative analysis. Meta-analysis revealed significant associations between the GLIM-defined pooled malnutrition (HR=1.75, 95%CI=1.43 to 2.15), moderate malnutrition (HR=1.44, 95%CI=1.29 to 1.62) and severe malnutrition (HR=1.79, 95%CI=1.58 to 2.02) with all-cause mortality. Sensitivity analysis supported the robustness of these associations. The between-study heterogeneity was low (all I² < 50 %) and study quality assessed with NOS was high (all scores > 6). The evidence quality by the GRADE tool was very low.

CONCLUSIONS: Our meta-analysis suggests a significant negative association of malnutrition, as defined by the GLIM, with overall survival in patients with cancer. However, definitive conclusions cannot be precluded due to the low quality of the source data. This article is protected by copyright. All rights reserved.

PMID:36371641 | DOI:10.1002/jpen.2463

J Child Adolesc Psychiatr Nurs. 2022 Nov 12. doi: 10.1111/jcap.12401. Online ahead of print.

ABSTRACT

PROBLEM: (1) To identify the factors associated with self-reported smartphone addiction (SRSA) among adolescents in the face of the COVID-19 pandemic; and (2) to analyze the adolescents’ perception of these factors related to SRSA.

METHODS: A mixed-method study with a sequential explanatory design, carried out with Brazilian adolescents aged between 15 and 18 years old.

FINDINGS: The prevalence of SRSA was 56.37%, and the variables that remained in the final model of association were as follows: public schools; longer smartphone use during the COVID-19 pandemic; number of hours connected to the smartphone; preference for sleeping during the day; use of the device immediately after waking up, smartphone use after 9 p.m., amount of sleep less than 8 h a day; and smartphone use during meals. Sequentially, after analyzing the data obtained in the focus groups, it was possible to describe how adolescents perceive the intensification of smartphone uses, its repercussions, and activities carried out on it during the pandemic.

CONCLUSIONS: The pandemic had repercussions on the behavior established with the smartphone, such as time and period of use, being associated with the SRSA. In addition, it was found that such conditions also affect the adolescents’ sleep quality, diet, and studies.

PMID:36371611 | DOI:10.1111/jcap.12401