This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Background Noninvasive prenatal tests (NIPTs) detect fetal chromosomal anomalies with high clinical sensitivity and specificity. We examined the performance of a paired-end sequencing-based NIPT in the detection of genome-wide fetal chromosomal anomalies including common trisomies, sex chromosomal aneuploidies (SCA), rare autosomal aneuploidies (RAAs), and partial deletions/duplications ≥7 Mb. Methods Frozen plasma samples from pregnant women were tested using the VeriSeq NIPT Solution v2 assay. All samples were previously tested with a laboratory-developed NIPT and had known clinical outcomes. Individuals performing the sequencing were blinded to clinical outcome data. Clinical sensitivity and specificity were determined for basic (chromosomes 21, 18, 13, X, and Y) and genome-wide screening modes. Results Of 2335 samples that underwent genome-wide analysis, 28 did not meet QC requirements, resulting in a first-pass assay failure rate of 1.2%. Basic screening analysis, excluding known mosaics, correctly classified 130/130 trisomy 21 samples (sensitivity >99.9%, 95% confidence interval [CI] 97.1%–100%), 41/41 trisomy 18 samples (sensitivity >99.9%, 95% CI 91.4%–100%), and 26/26 trisomy 13 samples (sensitivity >99.9%, 95% CI 87.1%–100%) with 6 false-positive results; specificities ≥99.90% were reported for all 3 trisomies. Concordance for SCAs ranged from 90.5%–100%. Genome-wide screening analysis including known mosaics correctly classified 27/28 RAAs and 20/27 partial deletions/duplications with a specificity of 99.80% for both anomalies, and an overall genome-wide specificity for all anomalies of 99.34%. Conclusions The VeriSeq NIPT Solution v2 assay enables accurate identification of fetal aneuploidy, allowing detection of genome-wide fetal chromosomal anomalies with high clinical sensitivities and specificities and a low assay failure rate. Clinical Trial Notification [CTN] identification number [ID]: CT-2018-CTN-01585-1 v1, Protocol: NIPT T05 002.

No abstract

No abstract

PurposeTo validate a next-generation sequencing (NGS)-based companion diagnostic using the MiSeqDx® sequencing instrument to simultaneously detect 56 RAS mutations in DNA extracted from formalin-fixed paraffin-embedded metastatic colorectal cancer (mCRC) tumor samples from the PRIME study. The test’s ability to identify patients with mCRC likely to benefit from panitumumab treatment was assessed.MethodsSamples from PRIME, which compared first-line panitumumab + FOLFOX4 with FOLFOX4, were processed according to predefined criteria using a multiplex assay that included input DNA qualification, library preparation, sequencing, and the bioinformatics reporting pipeline. NGS mutational analysis of KRAS and NRAS exons 2, 3, and 4 was performed and compared with Sanger sequencing.ResultsIn 441 samples, positive percent agreement of the Extended RAS Panel with Sanger sequencing was 98.7% and negative percent agreement was 97.6%. For clinical validation (n = 528), progression-free survival (PFS) and overall survival (OS) were compared between patients with RAS mutations (RAS Positive) and those without (RAS Negative). Panitumumab + FOLFOX4 improved PFS in RAS Negative patients (P = 0.02). Quantitative interaction testing indicated the treatment effect (measured by the hazard ratio of panitumumab + FOLFOX4 versus FOLFOX4) differed for RAS Negative versus RAS Positive for PFS (P = 0.0038) and OS (P = 0.0323).ConclusionsNGS allows for broad, rapid, highly specific analyses of genomic regions. These results support use of the Extended RAS Panel as a companion diagnostic for selecting patients for panitumumab, and utilization is consistent with recent clinical guidelines regarding mCRC RAS testing. Overall, approximately 13% more patients were detected with the Extended RAS Panel versus KRAS exon 2 alone.Clinical trial registry identifierNCT00364013 (ClinicalTrials.gov).Electronic supplementary materialThe online version of this article (10.1007/s00432-018-2688-3) contains supplementary material, which is available to authorized users.

Purpose We tested whether short-term vitamin D supplementation improves insulin resistance in patients with kidney disease, a condition with little intrinsic vitamin D activity. Methods PubMed, Embase and CENTRAL were searched for relevant observational studies and randomized clinical trials (RCTs). Random effects models were employed for meta-analysis and effect sizes were summarized as standardized mean difference (SMD) with 95% confidence intervals. Separate analyses were done for RCTs and non-randomized intervention studies (NRIS). Results Seventeen studies (5 RCTs and 12 NRIS) were included. The meta-analysis population (n=131) was mostly middle aged (40–50 years), male and non-diabetic, and on hemodialysis. The duration (4–12 weeks) and type of supplementation varied between studies. Among RCTs, compared to placebo, vitamin D supplementation was associated with significant decrease in fasting glucose [SMD −1.13,( −2.11 to −0.11)] and PTH levels [SMD −1.50,(−2.95 to −0.04)] but no difference in fasting insulin levels [SMD 1.32, (−0.15 to 2.79). Among NRIS, there was only a significant decrease in PTH levels [SMD −1.68, (−2.55 to −0.82)] between pre and post-vitamin D treatment levels. Conclusions Short term (4–12 weeks) supplementation with vitamin D is associated with lower fasting glucose levels in ESRD with no change in fasting insulin levels. However, the findings from this study are limited by the studies that were used in the meta-analysis, which were mostly small, used multiple different vitamin D compounds and dosing regimens, had large heterogeneity and funnel plots showed there was a dearth of studies with null or negative finding. Therefore, larger randomized clinical trials need to be performed to answer this important clinical question.

Biomarkers assessing cardiovascular function can encompass a wide range of biochemical or physiological measurements. Medical tests that measure biomarkers are typically evaluated for measurement validation and clinical performance in the context of their intended use. General statistical principles for the evaluation of medical tests are discussed in this paper in the context of heart failure. Statistical aspects of study design and analysis to be considered while assessing the quality of measurements and the clinical performance of tests are highlighted. A discussion of statistical considerations for specific clinical uses is also provided. The remarks in this paper mainly focus on methods and considerations for statistical evaluation of medical tests from the perspective of bias and precision. With such an evaluation of performance, healthcare professionals could have information that leads to a better understanding on the strengths and limitations of tests related to heart failure.

No abstract