Tag: statistics

Methods Mol Biol. 2024;2715:431-470. doi: 10.1007/978-1-0716-3445-5_27.

ABSTRACT

Structural studies of bio-complexes using single particle cryo-Electron Microscopy (cryo-EM) is nowadays a well-established technique in structural biology and has become competitive with X-ray crystallography. Development of digital registration systems for electron microscopy images and algorithms for the fast and efficient processing of the recorded images and their following analysis has facilitated the determination of structures at near-atomic resolution. The latest advances in EM have enabled the determination of protein complex structures at 1.4-3 Å resolution for an extremely broad range of sizes (from ~100 kDa up to hundreds of MDa (Bartesaghi et al., Science 348(6239):1147-1151, 2015; Herzik et al., Nat Commun 10:1032, 2019; Wu et al., J Struct Biol X 4:100020, 2020; Zhang et al., Nat Commun 10:5511, 2019; Zhang et al., Cell Res 30(12):1136-1139, 2020; Yip et al., Nature 587(7832):157-161, 2020; https://www.ebi.ac.uk/emdb/statistics/emdb_resolution_year )). In 2022, nearly 1200 structures deposited to the EMDB database were at a resolution of better than 3 Å ( https://www.ebi.ac.uk/emdb/statistics/emdb_resolution_year ).To date, the highest resolutions have been achieved for apoferritin, which comprises a homo-oligomer of high point group symmetry (O432) and has rigid organization together with high stability (Zhang et al., Cell Res 30(12):1136-1139, 2020; Yip et al., Nature 587(7832):157-161, 2020). It has been used as a test object for the assessments of modern cryo-microscopes and processing methods during the last 5 years. In contrast to apoferritin bacterial secretion systems are typical examples of multi protein complexes exhibiting high flexibility owing to their functions relating to the transportation of small molecules, proteins, and DNA into the extracellular space or target cells. This makes their structural characterization extremely challenging (Barlow, Methods Mol Biol 532:397-411, 2009; Costa et al., Nat Rev Microbiol 13:343-359, 2015). The most feasible approach to reveal their spatial organization and functional modification is cryo-electron microscopy (EM). During the last decade, structural cryo-EM has become broadly used for the analysis of the bio-complexes that comprise multiple components and are not amenable to crystallization (Lyumkis, J Biol Chem 294:5181-5197, 2019; Orlova and Saibil, Methods Enzymol 482:321-341, 2010; Orlova and Saibil, Chem Rev 111(12):7710-7748, 2011).In this review, we will describe the basics of sample preparation for cryo-EM, the principles of digital data collection, and the logistics of image analysis focusing on the common steps required for reconstructions of both small and large biological complexes together with refinement of their structures to nearly atomic resolution. The workflow of processing will be illustrated by examples of EM analysis of Type IV Secretion System.

PMID:37930544 | DOI:10.1007/978-1-0716-3445-5_27

Target Oncol. 2023 Nov 6. doi: 10.1007/s11523-023-01008-x. Online ahead of print.

ABSTRACT

BACKGROUND: Delta-like ligand 3 (DLL3), a member of the Notch pathway, has been identified as a potential therapeutic target as it is highly expressed in small cell lung cancer (SCLC), a subtype accounting for 15% of lung cancer cases.

OBJECTIVE: A systematic literature review (SLR) was conducted to understand the prevalence and prognostic impact of DLL3 expression on survival of patients with SCLC and treatment response.

PATIENTS AND METHODS: Systematic literature searches were conducted across multiple databases to capture studies of any SCLC population that evaluated DLL3 expression. Specific outcomes of interest included prevalence of DLL3 expression, method of expression analysis, and impact on outcome, including treatment response and survival (overall, progression-free, disease-free) according to varying levels of DLL3 expression/positivity. Standard risk of bias tools were used to evaluate study quality.

RESULTS: Among the 30 included studies, the most common DLL3 testing method was immunohistochemistry (N = 26, 86.7%). For comparability, results focused on the 13 (22.3%) studies that used the Ventana DLL3 (SP347) immunohistochemistry assay. The prevalence of DLL3 positivity ranged from 80.0-93.5% for studies using a threshold of ≥ 1% of tumor cells (N = 4) and 58.3-91.1% for studies with a ≥ 25% threshold (N = 4). DLL3 expression was generally categorized as high using cutoffs of ≥ 50% (prevalence range: 45.8-79.5%; N = 6) or ≥ 75% (prevalence range: 47.3-75.6%; N = 5) of cells with positivity. Two studies used an H-score of ≥ 150 to define high DLL3 expression with prevalence ranging from 33.3-53.1%. No consistent associations were seen between DLL3 expression level and patient age, sex, smoking history, or disease stage. Two studies reported change in DLL3 expression category (high versus low) before and after chemotherapy. No statistically significant differences were reported between DLL3 expression groups and survival (overall, progression-free, or disease-free) or treatment response.

CONCLUSIONS: There is a high prevalence of DLL3 expression in SCLC. Further research and analytical methods may help to characterize different populations of patients with SCLC based on DLL3 expression. While no significant prognostic factor in the included studies was identified, additional cohort studies using standardized methodology, with longer follow-up, are needed to better characterize any potential differences in patient survival or response by DLL3 expression level in SCLC.

PMID:37930513 | DOI:10.1007/s11523-023-01008-x

J Biopharm Stat. 2023 Nov 6:1-15. doi: 10.1080/10543406.2023.2275755. Online ahead of print.

ABSTRACT

Clinical trialists have long been searching for approaches to increase statistical power without increasing sample size. Conventional wait-list controlled (WLC) trials are limited to two trial arms and two or three repeated measurements per person. These features limit statistical power. Furthermore, their analysis is usually based on analysis of covariance or mixed effects modelling, with a focus on estimating treatment effect at one time-period after initiation of therapy. We propose two 3-arm WLC trial designs together with a mixed-effects analysis framework. The designs require three or four repeated measurements per person. The analytic framework defines up to three treatment effect estimands, representing the effects at one to three time-periods after initiation of therapy. The precision (inverse of variance) of the treatment effect estimators in the new and conventional trial designs are analytically derived and evaluated in simulations. The results are interpreted in the context of a cognitive training trial in older people. The proposed designs and analysis methods increase the precision level of treatment effect estimators as compared to conventional designs and analyses. Given a target level of statistical power, the proposed methods require a smaller number of participants per trial than the conventional methods, without necessarily increasing the number of measurements per trial. Furthermore, the proposed analytic framework sheds light on the treatment effects at different times after initiation of therapy, which is not usually considered in conventional WLC trial analysis. In situations that a WLC trial is appropriate, the 3-arm designs are useful alternatives to existing 2-arm designs.

PMID:37929703 | DOI:10.1080/10543406.2023.2275755

Health Technol Assess. 2023 Oct;27(23):1-108. doi: 10.3310/VPDT7105.

ABSTRACT

BACKGROUND: Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics.

OBJECTIVES: To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia.

DESIGN: Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued).

SETTING: Twenty-six UK secondary care centres.

PARTICIPANTS: Eligibility: probable or possible Alzheimer’s disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45.

INTERVENTIONS: Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo.

OUTCOME MEASURES: Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months.

RANDOMISATION AND BLINDING: Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation.

RESULTS: Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (-1.74, 95% confidence interval -7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups.

LIMITATIONS: Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes.

CONCLUSIONS: The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation.

FUTURE WORK: Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful.

STUDY REGISTRATION: This trial is registered as ISRCTN17411897/NCT03031184.

FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information.

PMID:37929672 | DOI:10.3310/VPDT7105

J Am Heart Assoc. 2023 Nov 6:e030012. doi: 10.1161/JAHA.123.030012. Online ahead of print.

ABSTRACT

Background We performed a meta-analysis of reconstructed time-to-event data from randomized controlled trials (RCTs) and propensity-score matched (PSM) studies comparing transcatheter versus surgical aortic valve replacement (TAVR versus SAVR) to evaluate midterm outcomes in patients considered low risk for SAVR. Methods and Results Study-level meta-analysis of reconstructed time-to-event data from Kaplan-Meier curves of RCTs and PSM studies published by December 31, 2022 was conducted. Eight studies (3 RCTs, 5 PSM studies) met our eligibility criteria and included 5444 patients; 2639 patients underwent TAVR, and 2805 patients underwent SAVR. TAVR showed a higher risk of all-cause mortality at 8 years of follow-up (hazard ratio [HR] 1.22, [95% CI, 1.03-1.43], P=0.018). Up to 2 years of follow-up, TAVR was not inferior to SAVR (HR, 1.08 [95% CI, 0.89-1.31], P=0.448); however, we observed a statistically significant difference after 2 years with higher mortality with TAVR (HR, 1.51 [95% CI, 1.14-2.00]; P=0.004). This difference was driven by PSM studies; our sensitivity analysis showed a statistically significant difference between TAVR and SAVR when we included only PSM studies (HR, 1.41 [95% CI, 1.16-1.72], P=0.001) but no statistically significant difference when we included only RCTs (HR, 0.89 [95% CI, 0.69-1.16], P=0.398). Conclusions In comparison with TAVR, SAVR appeared to be associated with improved survival beyond 2 years in low-risk patients. However, the survival benefit of SAVR was observed only in PSM studies and not in RCTs. The addition of data from ongoing RCTs as well as longer follow-up in previous RCTs will help to confirm if there is a difference in mid- and long-term survival between TAVR versus SAVR in the low-risk population.

PMID:37929669 | DOI:10.1161/JAHA.123.030012

Eur J Haematol. 2023 Nov 6. doi: 10.1111/ejh.14131. Online ahead of print.

ABSTRACT

Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag. While outcomes are favorable in younger patients, older patients (>60) have significantly worse long-term survival. The dose of ATG is often reduced in older patients and those with multiple comorbidities given concerns for tolerability. The efficacy and safety of dose-attenuated IST in this population is largely undescribed. We performed a retrospective review of patients with AA treated with IST. Our analysis was confounded by changes in practice patterns and the introduction of eltrombopag. We identified 53 patients >60 years old, of which, 20 received dose-attenuated IST, with no statistically significant difference in overall survival between full and attenuated dose cohorts. Overall response rates in both cohorts were similar at 6 months at 71% and 68%. There were more documented infectious complications in the full dose cohort (13 vs. 3). This supports the consideration of dose-attenuated IST in older patients with concerns about tolerance of IST. Lastly, our data confirmed favorable outcomes of younger patients receiving IST, especially in combination with eltrombopag.

PMID:37929654 | DOI:10.1111/ejh.14131

Am J Med Genet C Semin Med Genet. 2023 Nov 6:e32075. doi: 10.1002/ajmg.c.32075. Online ahead of print.

ABSTRACT

Our current understanding of adaptation in families of individuals with Down syndrome (DS) is based primarily on findings from studies focused on participants from a single country. Guided by the Resiliency Model of Family Stress, Adjustment, and Adaptation, the purpose of this cross-country investigation, which is part of a larger, mixed methods study, was twofold: (1) to compare family adaptation in 12 countries, and (2) to examine the relationships between family variables and family adaptation. The focus of this study is data collected in the 12 countries where at least 30 parents completed the survey. Descriptive statistics were generated, and mean family adaptation was modeled in terms of each predictor independently, controlling for an effect on covariates. A parsimonious composite model for mean family adaptation was adaptively generated. While there were cross-country differences, standardized family adaptation mean scores fell within the average range for all 12 countries. Key components of the guiding framework (i.e., family demands, family appraisal, family resources, and family problem-solving communication) were important predictors of family adaptation. More cross-country studies, as well as longitudinal studies, are needed to fully understand how culture and social determinants of health influence family adaptation in families of individuals with DS.

PMID:37929633 | DOI:10.1002/ajmg.c.32075

Int J Rheum Dis. 2023 Nov 6. doi: 10.1111/1756-185X.14905. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the risk of all-cause, specific mortality among patients with fibromyalgia, which is a controversial topic.

METHODS: We conducted a thorough search for cohort studies across the PubMed, Cochrane Library, and Embase databases, from their inception to 1 March 2023, using medical subject headings and relevant keywords. All data were meticulously analyzed using Stata statistical software version 16.0. The protocol was registered on PROSPERO (CRD42023402337).

RESULTS: After analyzing seven cohort studies involving 152 933 individuals published between 2001 and 2020, we found no clear evidence linking fibromyalgia or widespread pain to all-cause mortality risk (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.81-1.53; I² = 82.6%, p = .505). However, our subgroup analysis revealed that the risk of suicide was significantly higher in fibromyalgia patients compared with non-fibromyalgia patients (OR 5.39, 95% CI 2.16-13.43; I² = 69.9%, p < .05).

CONCLUSIONS: Our research did not discover any proof indicating a link between fibromyalgia or widespread pain and all-cause mortality. However, it is worth noting that there may be a potential correlation between individuals with fibromyalgia or widespread pain and a higher likelihood of suicide. As we had a limited number of participants in our study, further research is necessary to thoroughly investigate the relationship between these factors.

PMID:37929630 | DOI:10.1111/1756-185X.14905

Int J Lang Commun Disord. 2023 Nov 6. doi: 10.1111/1460-6984.12974. Online ahead of print.

ABSTRACT

BACKGROUND: The COVID-19 pandemic resulted in rapid changes to head and neck cancer (HNC) services. Multidisciplinary team (MDT) face-to-face appointments were converted to telehealth appointments (telephone and video-call) to reduce the risk of COVID-19 transmission. The literature exploring HNC patient experience of these appointment types is limited.

AIMS: To explore patient experience of telehealth appointments at one UK centre during the COVID-19 pandemic, as well as the variables that may influence patient preference for virtual or face-to-face appointments.

METHODS & PROCEDURES: A survey-based study design was used, with closed questions and open text options to capture the views of the participants. Quantitative data were analysed using descriptive statistics. Open text data was used to add depth to the findings.

OUTCOMES & RESULTS: A total of 23 participant surveys were returned. Six categories were identified: Usability; Information receiving & giving; Satisfaction; Emotions and comfort; Rapport; and Travel time and cost. Overall, participants gave positive responses to each category and indicated that telehealth appointments met their needs. Areas for clinical consideration are highlighted. Variables such as age, travel distance from hospital site, fear of COVID-19 and information technology (IT) access did not appear to influence patient preference for appointment type.

CONCLUSIONS & IMPLICATIONS: Going forward, telehealth may be considered for use in combination with face-to-face appointments in the HNC pathway. Areas for further development include a ‘telehealth screening tool’ that may help to identify those patients most appropriate for these appointment types, or who require support to access them.

WHAT THIS PAPER ADDS: What is already known on this subject The COVID-19 pandemic resulted in major disruption to HNC centres across the world. Services adapted to meet the needs of patients with many implementing telehealth into pathways. Studies exploring telehealth in speech and language therapy (SLT) services with the HNC population indicate positive results. It is clear telehealth has a role in modern healthcare and should not be viewed as a temporary solution to the pandemic. It is, however, recognized that embedding telehealth into pathways is not straightforward and requires ongoing review and evaluation, which includes patient and clinician perceptions. What this study adds to the existing knowledge The service evaluation gives insight into HNC patient experience of telehealth appointments for MDT clinics (led by SLT, dietician and clinical nurse specialist) during the COVID-19 pandemic. Overall, patients report a positive experience of telehealth in the HNC pathway and are willing to accept this platform into their healthcare. Areas for clinical consideration are highlighted. What are the actual and clinical implications of this work? This findings of this service evaluation can be used to support the co-design of HNC pathways which embed telehealth as an option for patients. Areas that were important to the participants are highlighted; this includes the timing of telehealth appointments in the pathway, the need to meet the MDT face to face and the positive benefit of cost savings. The authors suggest a telehealth appointment screening tool as an area for future development.

PMID:37929624 | DOI:10.1111/1460-6984.12974

Int J Lang Commun Disord. 2023 Nov 6. doi: 10.1111/1460-6984.12972. Online ahead of print.

ABSTRACT

BACKGROUND: The use of telepractice in aphasia research and therapy is increasing in frequency. Teleassessment in aphasia has been demonstrated to be reliable. However, neuropsychological and clinical language comprehension assessments are not always readily translatable to an online environment and people with severe language comprehension or cognitive impairments have sometimes been considered to be unsuitable for teleassessment.

AIM: This project aimed to produce a battery of language comprehension teleassessments at the single word, sentence and discourse level suitable for individuals with moderate-severe language comprehension impairments.

METHODS: Assessment development prioritised response consistency and clinical flexibility during testing. Teleassessments were delivered in PowerPoint over Zoom using screen sharing and remote control functions. The assessments were evaluated in 14 people with aphasia and 9 neurotypical control participants. Modifiable assessment templates are available here: https://osf.io/r6wfm/.

MAIN CONTRIBUTIONS: People with aphasia were able to engage in language comprehension teleassessment with limited carer support. Only one assessment could not be completed for technical reasons. Statistical analysis revealed above chance performance in 141/151 completed assessments.

CONCLUSIONS: People with aphasia, including people with moderate-severe comprehension impairments, are able to engage with teleassessment. Successful teleassessment can be supported by retaining clinical flexibility and maintaining consistent task demands.

WHAT THIS PAPER ADDS: What is already known on the subject Teleassessment for aphasia is reliable but assessment of auditory comprehension is difficult to adapt to the online environment. There has been limited evaluation of the ability of people with severe aphasia to engage in auditory comprehension teleassessment. What this paper adds to existing knowledge Auditory comprehension assessment can be adapted for videoconferencing administration while maintaining clinical flexibility to support people with severe aphasia. What are the potential or actual clinical implications of this work? Teleassessment is time and cost effective and can be designed to support inclusion of severely impaired individuals.

PMID:37929612 | DOI:10.1111/1460-6984.12972