ArCH: improving the performance of clonal hematopoiesis variant calling and interpretation.

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. RESULTS: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. AVAILABILITY AND IMPLEMENTATION: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH.

Accuracy of Cytologic vs Histologic Specimens for Assessment of Programmed Cell Death Ligand-1 Expression in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression on tumor cells, evaluated by immunohistochemistry, guides the use of immunotherapy in advanced non-small cell lung cancer (NSCLC). RESEARCH QUESTION: What is the sensitivity and specificity of PD-L1 testing performed in cytologic vs paired histologic specimens in patients with NSCLC? STUDY DESIGN AND METHODS: The MEDLINE, Embase, Web of Science, and Cochrane Library databases were searched through June 1, 2021. The primary outcome was pooled sensitivity and specificity of PD-L1 testing performed on cytologic specimens compared with the reference standard of histologic specimens, analyzed at the PD-L1 expression cutoffs (tumor proportion score) ≥ 1% and ≥ 50%. Pooled sensitivity and specificity, and associated 95% CIs, were estimated using bivariate generalized linear mixed models. RESULTS: Twenty-six articles were included, encompassing a total of 1,064 pairs of histology specimens and cytology cell blocks, and 267 pairs of histology specimens and direct smears. Among these, 946 paired specimens were acquired without interval treatment between the collection of histology and cytology samples. The pooled sensitivity and specificity of cytology specimens compared with paired histology specimens at the PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.77-0.89) and 0.88 (95% CI, 0.82-0.93), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.78 (95% CI, 0.69-0.86) and 0.94 (95% CI, 0.91-0.96), respectively. When only paired specimens acquired without interval treatment were considered, the pooled sensitivity and specificity of cytology specimens at PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.76-0.90) and 0.89 (95% CI, 0.82-0.94), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.80 (95% CI, 0.71-0.89) and 0.94 (95% CI, 0.91-0.96), respectively. INTERPRETATION: Cytologic specimens provide an accurate assessment of PD-L1 expression in most patients with NSCLC, at both ≥ 1% and ≥ 50% cutoffs, when compared with histologic specimens. TRIAL REGISTRATION: PROSPERO; No.: CRD42020153279; URL: https://www.crd.york.ac.uk/prospero/.

Effects of training and support programs for leaders of illness-based support groups: commentary and updated evidence.

BACKGROUND: Peer-led support groups play an important role in supporting people with chronic diseases. They may be particularly important for people with rare diseases who typically do not have access to professional support options that focus on their disease-specific needs. Many peer-led support groups in rare diseases, however, are not sustained, and many patients do not have access to support groups. Training and education for peer support group leaders could address barriers to initiating and sustaining groups, but there is little evidence on the effectiveness of support group leader training programs. A previous systematic review evaluated the effects of training programs for peer leaders of support groups for people with medical illness on leader and support group outcomes, but it identified only one randomized controlled trial (RCT) that compared high- and low-resource training programs for cancer support group leaders. The trial did not find evidence that the high-resource program was more effective, but was limited by a small sample size and serious methodological limitations. To meet the needs of people living with the rare autoimmune connective tissue disease scleroderma, the Scleroderma Patient-centered Intervention Network has partnered with patient organizations to develop the Scleroderma Support group Leader EDucation Program, and a full-scale RCT to test the effectiveness of the program is planned. To verify the need for such a trial, we updated the previous systematic review. UPDATED EVIDENCE: Review methods for the update were unchanged from the initial review. The updated database search yielded 1504 unique citations in addition to the 9757 assessed for eligibility in the previous review. All additional citations identified in the updated search were excluded at the title and abstract review stage. CONCLUSIONS: Our systematic review update found that there is presently insufficient evidence on the effectiveness of training and support programs for peer leaders of disease-based support groups, highlighting the need for well-designed and rigorously conducted RCTs to examine the effects of training for peer leaders of support groups, especially in a rare disease context. The Scleroderma Patient-centered Intervention Network's trial of the Scleroderma Support group Leader EDucation Program will serve as such a trial. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018096369.

The association of sociodemographic and disease variables with hand function: a Scleroderma Patient-centered Intervention Network cohort study.

OBJECTIVES: Impaired hand function in systemic sclerosis (SSc) is a primary cause of disability and contributes diminished health-related quality of life. The objective of the present study was to evaluate sociodemographic, lifestyle, and disease-related factors independently associated with hand function in SSc. METHODS: Patients enrolled in the Scleroderma Patient-centered Intervention Network Cohort who completed baseline study questionnaires between March 2014 and September 2017 were included. Hand function was measured using the Cochin Hand Function Scale (CHFS). Multiple linear regression analysis was used to identify independent correlates of impaired hand function. RESULTS: Among 1193 participants (88% female), the mean CHFS score was 13.3 (SD=16.1). Female sex (standardised regression coefficient, beta (ß)=.05), current smoking (ß=.07), higher BMI (ß=.06), diffuse SSc (ß=0.14), more severe Raynaud's scores (ß=.23), more severe finger ulcer scores (ß=.23), moderate (ß=0.19) or severe small joint contractures (ß=.20), rheumatoid arthritis (ß=0.07), and idiopathic inflammatory myositis (ß=0.06) were significantly associated with higher CHFS scores (more impaired hand function). Consumption of 1-7 alcoholic drinks per week (ß=-0.07) was associated with lower CHFS scores (less impaired hand function) compared to no drinking. CONCLUSIONS: Multiple factors are associated with hand function in SSc. The presence of moderate or severe small joint contractures, the presence of digital ulcers, and severity of Raynaud's phenomenon had the largest associations. Effective interventions are needed to improve the management of hand function in patients with SSc.