Pairwise Concordance Research Articles

Surgically treated degenerative disk disease in twins.

Previous studies have suggested that genetic factors are important in the development of degenerative disk disease (DDD). However, the concordance rates for the phenotypes requiring surgery are unknown. The purpose of this study was to determine the concordance rates for DDD requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. Patients, aged between 18 and 85years, operated for DDD between 1996 and 2022 were identified in the national Swedish spine register (Swespine) and matched with the Swedish twin registry (STR) to identify MZ and DZ twins. Pairwise and probandwise concordance rates were calculated. We identified 11,207 patients, 53% women, operated for DDD. By matching the Swespine patients with the STR, we identified 121 twin pairs (37 MZ and 84 DZ) where one or both twins were surgically treated for DDD. The total twin incidence for operated DDD was 1.1%. For DDD requiring surgery, we found no concordant MZ pair and no concordant DZ pair where both twins were operated for DDD. When we evaluated pairs where at least one twin was operated for DDD, we found two concordant MZ pairs (the co-twins were operated for spinal stenosis) and two concordant DZ pairs (one co-twin operated for spinal stenosis and one (co-twin operated for disk herniation). Our findings suggest that genetic factors are probably not a major etiologic component in most cases of DDD requiring surgery. The findings of this study can be used for counseling patients about the risk for requiring DDD surgery.

Surgically Treated Degenerative Lumbar Spine Diseases in Twins.

There is growing evidence to suggest a potential genetic component underlying the development and progression of lumbar spine diseases. However, the heritability and the concordance rates for the phenotypes requiring surgery for the common spine diseases lumbar spinal stenosis (LSS) and lumbar disc herniation (LDH) are unknown. The aim of this study was to determine the heritability and the concordance rates for LSS and LDH requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. Patients between 18 and 85 years of age who underwent surgery for LSS or LDH between 1996 and 2022 were identified in the national Swedish spine registry (LSS: 45,110 patients; LDH: 39,272 patients), and matched with the Swedish Twin Registry to identify MZ and DZ twins. Pairwise and probandwise concordance rates, heritability estimates, and MZ/DZ concordance ratios were calculated. We identified 414 twin pairs (92 MZ and 322 DZ pairs) of whom 1 or both twins underwent surgery for LSS. The corresponding number for LDH was 387 twin pairs (118 MZ and 269 DZ pairs). The probandwise concordance rate for LSS requiring surgery was 0.25 (26 of 105) (95% confidence interval [CI], 0.14 to 0.34) for MZ twins and 0.04 (12 of 328) (95% CI, 0.01 to 0.07) for DZ twins. The corresponding values for LDH requiring surgery were 0.03 (4 of 120) (95% CI, 0 to 0.08) and 0.01 (4 of 271) (95% CI, 0 to 0.04), respectively. The probandwise MZ/DZ concordance ratio was 6.8 (95% CI, 2.9 to 21.5) for LSS and 2.3 (95% CI, 0 to 8.9) for LDH. The heritability was significantly higher in LSS compared with LDH (0.64 [95% CI, 0.50 to 0.74] versus 0.19 [95% CI, 0.08 to 0.35]). Our findings suggest that genetic factors may play an important role in the risk of developing LSS requiring surgery, whereas heredity seems to be of less importance in LDH requiring surgery. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Stationarity and cycles in the energy consumption in the United States

The purpose of this paper is twofold: analyzing stationarity of energy consumption by source in the United States and studying their cycles and pairwise synchronization. We study a panel of nine time series of monthly energy consumption for the period 1973–2022. Four of the series (namely coal, natural gas, petroleum, and nuclear electric power consumption) are non-renewables, whereas the remaining ones (hydroelectric power, geothermal, biomass, solar, and wind energy consumption) are renewable energy sources. We employ a nonparametric, panel stationarity testing approach. The results indicate that most of the series may be trend-stationarity, with nuclear and geothermal energy consumption being the only exceptions. Additionally, a study on potential cycles in the series of energy consumption by source is carried out, and subsequently we analyze pairwise concordance between states of different energy sources and between states of energy sources and the business cycle. Significant correlations are detected in the latter analysis, which are positive in the case of fossil fuel sources and negative for two renewable sources, namely geothermal and biomass energy consumption.

35 Pairwise Concurrence Rates Between Standalone and Embedded Performance Validity Tests

Objective:Determine the classification concordance between a standalone performance validity test (PVT) and embedded PVTs from multiple cognitive domains.Participants and Methods:Participants were 106 patients (49.1% female; 69% white) that underwent neuropsychological evaluation at an outpatient university doctoral clinical psychology training and research clinic (M/SD: age = 32.38/11.95; education = 13.7/2.75). A comprehensive neuropsychological battery included the Medical Symptom Validity Test (MSVT) and embedded PVTs from different cognitive domains: attention - Wechsler Adult Intelligence Scale - Fourth Edition Reliable Digit Span and Digit Span age-corrected scaled score (DS ACSS); memory - California Verbal Learning Test, 3rd Edition (CVLT-3) Forced-Choice Recognition (FCR), executive functions -Wisconsin Card Sorting Test (WCST) Failure to Maintain Set (FMS); visual-spatial/construction -Rey Complex Figure Test (RCFT) Copy raw score; language - Boston Diagnostic Aphasia Examination Complex Ideation Material (CIM); and motor functions - Finger Tapping Test (FTT). All participants were administered the MSVT but not all participants were administered all seven embedded PVTs. Credible/noncredible classification concordance rates and kappa correlations (i.e., percentage of agreement) were computed for each pairwise PVT combination.Results:Twenty-two percent (n = 23) of the sample failed at least one PVT, with 17.0% (n = 18) failing at least two. DS ACSS was the embedded PVT with the highest MSVT concordance rate at 92.4% and a fair kappa coefficient of .39; WCST FMS had the lowest concordance with MSVT at 82.9% and a slight kappa coefficient of .19. The highest concordance among embedded PVTs from different cognitive domains was CVLT-3 FCR and RCFT Copy raw score at 89.7% with a fair kappa coefficient of .35; the lowest agreement among embedded PVTs was WCST FMS and FTT at 74.0% with a kappa coefficient of -.02. More conservative kappa coefficients among all pair-wise embedded PVT combinations from different cognitive domains ranged from -.02 to .36. For all standalone and embedded PVT pairwise concordance rates, only two fell below the recommended minimum agreement of 80%: FCR vs. FMS = 79.3% and FMS vs. FTT = 74.0%.Conclusions:Embedded PVTs across various cognitive domains have high agreement with a standalone PVT to aid in classifying noncredible performance, in the 83-92% range. Embedded PVTs from different cognitive domains also have mostly high agreement classification rates amongst themselves in aiding to determine noncredible performance, in the 74-90% range, with the lowest agreement rate between executive function and motor tests at 74%. More conservative kappa-based agreements between PVT pair-wise combinations were fairly consistent with other studies, with most being in the fair range. Finally, these findings indicate about a 17% base rate of noncredible cognitive performance in an outpatient university-based clinic.

Embryo ranking agreement between embryologists and artificial intelligence algorithms

To evaluate the degree of agreement of embryo ranking between embryologists and eight AI algorithms. Retrospective study PATIENTS: A total of 100 cycles with at least eight embryos were selected from the Weill Cornell Medicine database. For each embryo, the full-length time-lapse (TL) videos, as well as a single embryo image at 120 h, were given to five embryologists and eight AI algorithms for ranking. None MAIN OUTCOME MEASURE(S): Kendall rank correlation coefficient (Kendall's τ) RESULTS: Embryologists had a high degree of agreement in the overall ranking of 100 cycles with an average Kendall's tau (K-τ) of 0.70, slightly lower than the inter-embryologist agreement when using a single image or video (average K-τ = 0.78). Overall agreement between embryologists and the AI algorithms was significantly lower (average K-τ = 0.53) and similar to the observed low inter-AI algorithm agreement (average K-τ = 0.47). Notably, two of the eight algorithms had a very low agreement with other ranking methodologies (average K-τ = 0.05) and between each other (K-τ = 0.01). The average agreement in selecting the best-quality embryo (1/8 in 100 cycles with an expected agreement by random chance of 12.5%; CI95: 6-19%) was 59.5% among embryologists and 40.3% for six AI algorithms. The incidence of the agreement for the two algorithms with the low overall agreement was 11.7%. Agreement on selecting the same top-two embryos/cycle (expected agreement by random chance corresponds to 25.0%; CI95: 17-32%) was 73.5% among embryologists and 56.0% among AI methods excluding two discordant algorithms, which had an average agreement of 24.4%, the expected range of agreement by random chance. Intra-embryologist ranking agreement (single image vs. video) was 71.7% and 77.8% for single and top-two embryos, respectively. Analysis of average raw scores indicated that cycles with low diversity of embryo quality generally resulted in a lower overall agreement between the methods (embryologists and AI models). To our knowledge, this is the first study that evaluates the level of agreement in ranking embryo quality between different AI algorithms and embryologists. The different concordance methods were consistent and indicated that the highest agreement was intra-embryologist agreement, followed by inter-embryologist agreement. In contrast, the agreement between some of the AI algorithms and embryologists was similar to the inter-AI algorithm agreement, which also showed a wide range of pair-wise concordance. Specifically, two AI models showed intra- and inter-agreement at the level expected from random selection.

Hierarchical organization of spontaneous co-fluctuations in densely sampled individuals using fMRI.

Edge time series decompose functional connectivity into its framewise contributions. Previous studies have focused on characterizing the properties of high-amplitude frames (time points when the global co-fluctuation amplitude takes on its largest value), including their cluster structure. Less is known about middle- and low-amplitude co-fluctuations (peaks in co-fluctuation time series but of lower amplitude). Here, we directly address those questions, using data from two dense-sampling studies: the MyConnectome project and Midnight Scan Club. We develop a hierarchical clustering algorithm to group peak co-fluctuations of all magnitudes into nested and multiscale clusters based on their pairwise concordance. At a coarse scale, we find evidence of three large clusters that, collectively, engage virtually all canonical brain systems. At finer scales, however, each cluster is dissolved, giving way to increasingly refined patterns of co-fluctuations involving specific sets of brain systems. We also find an increase in global co-fluctuation magnitude with hierarchical scale. Finally, we comment on the amount of data needed to estimate co-fluctuation pattern clusters and implications for brain-behavior studies. Collectively, the findings reported here fill several gaps in current knowledge concerning the heterogeneity and richness of co-fluctuation patterns as estimated with edge time series while providing some practical guidance for future studies.

Application of a truncated ORF2 protein-based ELISA for diagnosis of hepatitis E in an endemic area.

Enterically transmitted waterborne hepatitis E (HE) caused due to hepatitis E virus (HEV) prevails as a significant public health problem endemic to India. Due to short-term viremia/fecal excretion and poor in vitro transmissibility of HEV, HE diagnosis depends on detection of specific IgM antibodies in serum. Present study evaluated performances of two in-house and six commercial IgM detection enzyme-linked immunosorbent assays (ELISAs) using sera collected from volunteers/acute hepatitis patients (n = 716). The in-house ELISAs were based on complete and truncated open reading frame 2 (ORF2) proteins containing neutralizing epitope/s region of genotype 1 HEV (ORF2p, 1-660 amino acid (a.a.) and T1NEp, 458-607 a.a., respectively). The commercial ELISAs included Wantai (China), MP Diagnostics (MPD) (Singapore), DIA.PRO Diagnostics (Italy), MBS (Italy), abia (Germany), and ImmunoVision (USA). T1NE ELISA showed 97.0% positive percent agreement (PPA), 99.4% negative percent agreement (NPA), and 98.6% concordance (κ = 0.97, P = 0.0000) with ORF2 ELISA. ORF2, T1NE, Wantai, and MPD ELISAs agreed on results for 88% of sera tested. Two percent sera showed reactivity in each combination of three and two of aforementioned four ELISAs. Remaining 8% sera were single ELISA reactive. PPA and NPA value ranges were 76.3-99.0% and 84.8-99.5%, respectively. Pairwise concordances between all the eight ELISAs ranged from 88.0 to 100% (κ: 0.74-1.00). Both the in-house ELISAs agreed better with Wantai over MPD ELISA. In conclusion, both ORF2 and T1NE ELISAs were equally efficient in diagnosing HEV infections. T1NEp proved to be an excellent tool in HE sero-diagnosis and is worth exploring in development of simple rapid tests. KEY POINTS: • In-house ELISA based on bacterially expressed neutralizing epitope/s region protein • In-house ELISA based on complete ORF2 protein expressed in insect cells • Comparison of two in-house and six commercial anti-HEV IgM antibody detection ELISAs.

A Quantitative Subarachnoid Hemorrhage Grading System, Including Supratentorial and Infratentorial Cisterns, With Multiplanar Computed Tomography Reformations.

BackgroundSubarachnoid hemorrhage (SAH) grading scales typically evaluate a limited number of cisterns on the axial plane. The goal of our study is to apply a simple quantitative yet comprehensive SAH grading scale to all major intracranial cisterns, including the infratentorial cisterns, with multiplanar computed tomography (CT) reformations.MethodologyWe performed a retrospective review of 94 consecutive cases of spontaneous SAH presenting within 72 hours of onset. SAH was categorized into five grades based on the short-axis thickness of SAH in 20 intracranial cisterns measured on the axial, coronal, and sagittal planes. Statistical analysis was performed for inter-rater agreement with kappa statistics, for inter-plane agreement by Spearman correlation statistics, and for inter-rater and inter-plane agreement by Pearson correlation statistics.ResultsThe extended kappa coefficient for the three reviewers across all 20 cisterns varied from 0.38 (0.27, 0.50) to 0.59 (0.52, 0.65) on the axial plane. The kappa coefficient for two reviewers varied from 0.46 (0.33, 0.59) to 0.70 (0.60, 0.80) on the coronal plane and from 0.35 (0.20, 0.49) to 0.87 (0.77, 0.96) on the sagittal plane. The average grade of cisterns per case demonstrated mostly excellent correlation between the imaging planes with Spearman correlation statistics (≥0.70). Pairwise concordance correlation coefficient of the total SAH score revealed agreement ranging from 0.81 to 0.90 in all three planes. Pearson correlation statistics of the average total SAH scores revealed excellent correlation among the three planes (≥0.91).ConclusionA simple quantitative SAH grading scale can be successfully applied to the supratentorial and infratentorial cisterns in three standard CT imaging planes.

Idiopathic scoliosis: a systematic review and meta-analysis of heritability.

PurposeIdiopathic scoliosis is the most common spinal deformity and affects 1–3% of children and adolescents. Idiopathic scoliosis may run in families and the purpose of this systematic review was to describe the degree of heritability.MethodsWe searched Medline, Web of Science and EMBASE for family and twin studies reporting heritability estimates for idiopathic scoliosis, or studies from which heritability estimates could be calculated. Reference lists were screened for additional papers. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered at PROSPERO (registration number: CRD42022307329).ResultsThe literature search identified 1134 reports. After full-text screening, nine eligible reports were included for data extraction. Seven were twin studies containing between 5 and 526 pairs, and two were family studies with 1149 and 2732 individuals, respectively. Quality was ‘good’ in four studies and ‘fair’ in five studies. In general, studies with radiograph-confirmed diagnosis reported higher heritability estimates than studies with self-reported diagnosis. Population-based twin studies reported lower heritability estimates than clinic-based twin studies. Family-based studies reported higher heritability estimates than twin studies. Pairwise concordance for scoliosis ranged from 0.11 to 1.00 in monozygotic twins and from 0 to 1.0 in dizygotic twins. A meta-analysis of three studies resulted in a narrow sense heritability estimate of 0.57 (95% CI: 0.29–0.86).ConclusionTwin and family studies indicate a hereditary component in idiopathic scoliosis, but study heterogeneity is large, and the degree of the heritability is uncertain. Nevertheless, known genetic variants associated with idiopathic scoliosis can still only explain a minor part of heritability.

Complexity of ballooned hepatocyte feature recognition: Defining a training atlas for artificial intelligence-based imaging in NAFLD

Histologically assessed hepatocyte ballooning is a key feature discriminating non-alcoholic steatohepatitis (NASH) from steatosis (NAFL). Reliable identification underpins patient inclusion in clinical trials and serves as a key regulatory-approved surrogate endpoint for drug efficacy. High inter/intra-observer variation in ballooning measured using the NASH CRN semi-quantitative score has been reported yet no actionable solutions have been proposed. A focused evaluation of hepatocyte ballooning recognition was conducted. Digitized slides were evaluated by 9 internationally recognized expert liver pathologists on 2 separate occasions: each pathologist independently marked every ballooned hepatocyte and later provided an overall non-NASH NAFL/NASH assessment. Interobserver variation was assessed and a 'concordance atlas' of ballooned hepatocytes generated to train second harmonic generation/two-photon excitation fluorescence imaging-based artificial intelligence (AI). The Fleiss kappa statistic for overall interobserver agreement for presence/absence of ballooning was 0.197 (95% CI 0.094-0.300), rising to 0.362 (0.258-0.465) with a ≥5-cell threshold. However, the intraclass correlation coefficient for consistency was higher (0.718 [0.511-0.900]), indicating 'moderate' agreement on ballooning burden. 133 ballooned cells were identified using a ≥5/9 majority to train AI ballooning detection (AI-pathologist pairwise concordance 19-42%, comparable to inter-pathologist pairwise concordance of between 8-75%). AI quantified change in ballooned cell burden in response to therapy in a separate slide set. The substantial divergence in hepatocyte ballooning identified amongst expert hepatopathologists suggests that ballooning is a spectrum, too subjective for its presence or complete absence to be unequivocally determined as a trial endpoint. A concordance atlas may be used to train AI assistive technologies to reproducibly quantify ballooned hepatocytes that standardize assessment of therapeutic efficacy. This atlas serves as a reference standard for ongoing work to refine how ballooning is classified by both pathologists and AI. For the first time, we show that, even amongst expert hepatopathologists, there is poor agreement regarding the number of ballooned hepatocytes seen on the same digitized histology images. This has important implications as the presence of ballooning is needed to establish the diagnosis of non-alcoholic steatohepatitis (NASH), and its unequivocal absence is one of the key requirements to show 'NASH resolution' to support drug efficacy in clinical trials. Artificial intelligence-based approaches may provide a more reliable way to assess the range of injury recorded as "hepatocyte ballooning".

Dosiomic feature comparison between dose-calculation algorithms used for lung stereotactic body radiation therapy.

To evaluate the reproducibility of dose-based radiomic (dosiomic) features between dose-calculation algorithms for lung stereotactic body radiation therapy (SBRT). We analyzed 105 patients with early-stage non-small cell lung cancer who underwent lung SBRT between March 2011 and December 2017. Radiation doses of 48, 60, and 70Gy were prescribed to the isocenter in 4-8 fractions. Dose calculations were performed using X-ray voxel Monte Carlo (XVMC) on the iPlan radiation treatment planning system (RTPS). Thereafter, the radiation doses were recalculated using the Acuros XB (AXB) and analytical anisotropic algorithm (AAA) on the Eclipse RTPS while maintaining the XVMC-calculated monitor units and beam arrangements. A total of 6808 dosiomic features were extracted without preprocessing (112 shape, 144 first-order, and 600 texture features) or with wavelet filters to eight decompositions (1152 first-order and 4800 texture features). Features with absolute pairwise concordance correlation coefficients-|CCcon|-values exceeding or equaling 0.85 were considered highly reproducible. Subgroup analyses were performed considering the wavelet filters and prescribed doses. The numbers of highly reproducible first-order and texture features were 34.8%, 26.9%, and 31.0% for the XVMC-AXB, XVMC-AAA, and AXB-AAA pairs, respectively. The maximum difference between the mean |CCcon| values was 0.70 and 0.11 for the subgroup analyses of wavelet filters and prescribed dose, respectively. The application of wavelet filter-based dosiomic analyses may be limited when using different types of dose-calculation algorithms for lung SBRT.

Perfusion measurement in brain gliomas using velocity-selective arterial spin labeling: comparison with pseudo-continuous arterial spin labeling and dynamic susceptibility contrast MRI.

To evaluate the performance of velocity-selective (VS) ASL among patients with untreated gliomas by comparing with both pseudo-continuous (PC) ASL and dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI). Forty-four consecutive patients with newly diagnosed glioma who underwent preoperative perfusion MRI including VSASL, PCASL, and DSC-PWI between 2017 and 2019 were retrospectively evaluated. Visual inspection was performed to evaluate the tumor signal intensity relative to gray matter based on 1-5 score criteria and weighted kappa was used to evaluate the pair-wise concordance between VSASL or PCASL and DSC-PWI. The relative tumor blood flow (rTBF) was measured from sampling intra-tumoral areas of hot-spot on the blood flow map and normalized against the contralateral normal gray matter blood flow. Linear regression and Bland-Altman analyses were performed to evaluate the correlation and agreement of rTBF measurements between ASL methods and DSC-PWI. The ROC analysis was constructed to determine the diagnostic performance of three perfusion methods for grading gliomas. TBF maps derived from VSASL were more comparable with DSC-PWI than PCASL on visual inspection (weighted kappa of 0.90 vs 0.68). In quantitative analysis, VSASL-rTBF yielded higher correlation with the values from DSC-PWI than PCASL-rTBF (R2 = 80% vs 47%, p < 0.001 for both). Both ASL and DSC-derived rTBF showed good distinction between low-grade and high-grade gliomas (p < 0.001). Compared to PCASL, VSASL yielded superior diagnostic sensitivity, specificity, and accuracy in glioma grading. VSASL showed great promise for accurate quantification of TBF and could potentially improve the diagnostic performance of ASL in preoperative grading of gliomas. •VSASL demonstrated a greater agreement with DSC-PWI than with PCASL on visual inspection and perfusion quantification. •VSASL showed a higher diagnostic sensitivity, negative predictive value, and accuracy than PCASL for glioma grading. •With the advantages of insensitivity to transit delay and no need of prescribing a labeling plane, VSASL could potentially improve the diagnostic performance of ASL for a more accurate, noninvasive quantification of TBF in patients with glioma.

A modified six-minute walk test (6MWT) for low-resource settings-a cross-sectional study

BackgroundThe 6 min walk test (6MWT) is a validated tool used to assess functional capacity in a variety of patient populations. Space constraints often limit the practicality of the 6MWT according to the standard (2002) American Thoracic Society protocol, and therefore, adaptations to this protocol are common with potential implications for research and clinical practice. Furthermore, such implications for research and clinical practice may be augmented in low-resourced settings. ObjectivesTo determine the agreement between the 6 min walk distance (6MWD) achieved on the standard 30 m (6MWT30), and a straight 10 m (6MWT10), or 10 m figure-of-eight (6MWTF8) configuration, respectively. MethodsA cross-sectional study was conducted in a socioeconomic challenged community. A heterogeneous sample of adults (n = 27) with non-communicable disease were randomized into performing the 6MWT10 (n = 15) or 6MWTF8 (n = 12), in addition to the standard 6MWT30. Pairwise comparison and concordance correlation coefficients were used to assess agreement. ResultsThe mean (SD) 6MWD30 was 437(42) meters, while the mean 6MWD10 was 371(57). The mean difference (SE; p-value) between the 6MWD30 and 6MWD10 was 67 m (8.6; p .01). The mean 6MWD30 was 424(67) meters, while the mean 6MWDF8 was 347(58). The mean difference between the 6MWD30 and 6MWDF8 was 77 m (6.0; p .01). Moderate concordance was found between the 6MWT30 and 6MWTF8 or 6MWD10, respectively. ConclusionsThe present data suggest that, independent of configuration, using a shorter pathway significantly reduced the 6MWD. Low-resource settings may benefit from contemporary measures of functional capacity more conducive to resource constraints, or standardization of the test when used in such settings.

Reference values for IGF-I serum concentration in an adult population: use of the VARIETE cohort for two new immunoassays.

ObjectiveMeasurement of IGF-I is important in the management of patients with growth hormone disorders. Here we aim to establish normative data for two new IGF-I assay kits based on a large random sample of the French general adult population.Subjects and methodsWe measured IGF-I in 911 healthy adults (18–90 years) with two immunoassays (ROCHE Elecsys® and IMMULITE-2000 calibrated against the new IS 02/2547). We compared the data with those of the six immunoassays (iSYS, LIAISON XL, IMMULITE-2000 calibrated against the first IS 87/518, IGF-I RIACT, Mediagnost ELISA, and Mediagnost RIA) that we reported previously. The pairwise concordance among the eight assays was assessed with Bland–Altman plots for both the IGF-1 raw data and the standard deviation scores (SDS), as well as with the percentage of observed agreement and the weighted Kappa coefficient for categorizing IGF-I SDS (ClinicalTrials.gov Identifier: NCT01831648).ResultsThe normative data included the range of values (2.5–97.5 percentiles) given by the two new IGF-I assays according to age group and sex. A formula for the SDS calculation is provided. As for the previous six assays, the lower limits of the reference intervals of the two new assays were similar, but the upper limits varied markedly. The pairwise concordances were only moderate (kappa 0.57).ConclusionsData obtained for these two new IGF-I immunoassays confirm that despite being obtained in the same large healthy population, the reference intervals of the eight commercial IGF-1 assay kits showed noteworthy differences. The agreement among the various methods was moderate to good.

Genetic determinants of immune-related adverse events in patients with melanoma receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAE susceptibility because the presentation of toxicity varies among patients and many do not develop irAEs despite continued ICI use. We sought to identify potential genetic markers conferring risk for irAEs. We conducted a pilot exploratory study in 89 melanoma patients who received ICIs (44 with irAEs, and 45 without irAEs after at least 1year from starting treatment). Genotyping was performed using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data were extracted using PLINK (v1.90b3.34) and processed for quality control. Population structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p < 1 × 10-3), and phenotype distribution for all study participants, resulting in seven population structure-based clusters. In the analytical stage, 599,931 variants in autosomal chromosomes were included for the association study. The association test was performed using an additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster. A total of 30 variants or single-nucleotide polymorphisms with p < 1 × 10-4 were identified; 12 were associated with an increased risk of irAEs, and the remaining 18 were associated with a decreased risk. Overall, nine of the identified single-nucleotide polymorphisms mapped to eight unique genes that have been associated with autoimmunity or inflammatory diseases. Several genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings and establish their potential functional relevance.

The impact of respiratory motion and CT pitch on the robustness of radiomics feature extraction in 4DCT lung imaging

Purpose/Objective(s)The precise radiomics analysis on thoracic 4DCT data is easily compromised by the respiratory motion and CT scan parameter setting, thus leading to the risk of overfitting and/or misinterpretation of data in AI-enabled therapeutic model building. In this study, we investigated the impact of respiratory amplitudes, frequencies and CT scan pitch settings within the thoracic 4DCT scan on robust radiomics feature selection. Materials/MethodsA Three-dimensional QUSARTM lung tumor phantom was used to simulate different respiratory amplitudes and frequencies along with different CT scan pitch settings. A total of 43 tumor respiratory patterns extracted from 43 patients with non-small cell lung cancer were used to drive the QUSARTM lung tumor phantom to mimic the human tumor motion. The 4DCT images of the QUSARTM lung tumor phantom with different respiratory patterns and different CT scan pitch setups were acquired for radiomics feature extraction. A static high-quality CT images of the phantom acquired were also used as a reference for radiomics feature extraction. The range of respiratory amplitudes was mimicked at 3mm at left and right (LR) and anterior and posterior (AP) directions and 3mm - 15 mm at the superior and inferior (SI) direction with an interval of 2 mm. The respiratory frequencies were set at 10, 11, 12, 13, 14, 15 and 20 beats per minute (BPMs), respectively. The CT scan pitches were set at 0.025, 0.048, 0.071, 0.93, 0.108, 0.14, 0.16, 0.18, 0.21, 0.23, and 0.25, respectively, which was based on a procedure described in Med. Phys. 30(1):88-97. The pairwise Concordance Correlation Coefficient (CCC) was used to determine the robustness of radiomics feature extraction via comparing the agreement in feature values between 1766 radiomics features extracted from each image acquired under different combinations of respiratory amplitudes and frequencies and CT scan pitches of 4DCT and those extracted from the static CT images. Results(1) When the respiratory amplitudes were at 3, 5, 7, 9, 12 and 15mm in the SI direction, the maximum CCC index could be achieved at the reconstructed 4DCT phase images of 60%, 70%, 30%, 20%, 60%~70% and 10%, respectively. Under these six amplitudes, the maximum intensity projection (MIP) and average intensity projection (AIP) images reconstructed show mean CCC values of 0.778 and 0.609, respectively, in pairwise radiomics feature extraction comparison between 4DCT and static CT. (2) When the respiratory amplitude was set at 12 mm in the SI direction, the maximum CCC index could be consistently achieved at the reconstructed 4DCT phase of 90% for the seven respiratory frequencies of 10, 11, 12, 13, 14, 15 and 20 BPMs, respectively. Under these respiratory states, the MIP and AIP images reconstructed show mean CCC values of 0.702 and 0.562, respectively. (3) When the respiratory amplitude was set at 12 mm and the respiratory frequency was set at 13 BPM, the maximum CCC index could be obtained at the reconstructed 4DCT phase of 90% for all scan pitches used except the 0% phase which was obtained at the pitch setting of 0.048. Under these CT scan pitch settings, the MIP and AIP images reconstructed show mean CCC values of 0.558 and 0.782, respectively. (4) The total number of robust features were 50, 34 and 35 with different respiratory amplitudes and phases and CT scanning pitch used (CCC values ≥ 0.99). ConclusionIn 4DCT, the respiratory amplitude, frequency and CT scan pitch are three limiting factors that greatly affect the robustness of radiomics feature extraction. The reconstructed 4DCT phases with better robustness along with suitable respiratory amplitude, frequency and CT scan pitch determined could be used to guide the breathing training for patients with lung cancer for radiation therapy to improve the robust radiomics feature extraction process.

A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer.

PIK3CA mutation frequency varies among breast cancer (BC) subtypes. Recent evidence suggests combination therapy with the PI3K inhibitor (PI3Ki) alpelisib and endocrine therapy (ET) improves response rates and progression-free survival (PFS) in PIK3CA-mutant, hormone receptor positive (HR+) BC versus ET alone; thus, better understanding the clinical and epidemiologic elements of these mutations is warranted. This systematic review characterizes the PIK3CA mutation epidemiology, type of testing approaches (e.g., liquid or tissue tumor biopsy), and stability/concordance (e.g., consistency in results by liquid versus solid tumor sample, by the same method over time) in patients with HR+/HER2– advanced (locally unresectable) or metastatic disease (HR+/HER2– mBC) and explores performance (e.g., pairwise concordance, sensitivity, specificity, or predictive value) of respective mutation findings. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts (i.e., AACR, ASCO, SABCS, ECCO, and ESMO conferences between 2014 and 2017) identified 39 studies of patients with HR+, HER2– mBC. The median prevalence of PIK3CA mutation was 36% (range: 13.3% to 61.5%); identified testing approaches more commonly used tissue over liquid biopsies and primarily utilized next-generation sequencing (NGS), polymerase chain reaction (PCR), or Sanger sequencing. There was concordance and stability between tissues (range: 70.4% to 94%) based on limited data. Given the clinical benefit of the PI3Ki alpelisib in patients with PIK3CA mutant HR+/HER2– mBC, determination of tumor PIK3CA mutation status is of importance in managing patients with HR+/HER2– mBC. Prevalence of this mutation and utility of test methodologies likely warrants PIK3CA mutation testing in all patients with this breast cancer subtype via definitive assessment of PIK3CA mutational status.

Characterization of background noise in MiSeq MPS data when sequencing human mitochondrial DNA from various sample sources and library preparation methods

Improved resolution of massively parallel sequencing (MPS) allows for the characterization of mitochondrial (mt) DNA heteroplasmy to levels previously unattainable with traditional sequencing approaches. An essential criterion for the reporting of heteroplasmy is the ability of the MPS method to distinguish minor sequence variants (MSVs) from system noise, or error. Therefore, an assessment of the background noise in the MPS method is desirable to identify the point at which reliable data can be reported. Substitution and sequence specific error (SSE) was evaluated for a variety of sample types and two library preparations. Substitution error rates ranged from 0.18 to 0.49 per 100 nucleotides with C positions generally having the highest rate of misincorporation. Comparison of error rates across sample types indicated a significant increase for samples with damaged DNA. The positions of error were varied across datasets (pairwise concordance 0–68%), but had greater consistency within the damaged samples (80–96%). The most commonly observed motif preceding error in forward reads was CCG, while GGT was most common in reverse reads, both consistent with previous findings. The findings illustrate that for datasets containing samples with damaged DNA, reporting thresholds for heteroplasmy may have to be modified and individual sites with error levels exceeding thresholds should be scrutinized. Collectively, the shifting error profiles observed across the various sample types and library preparation methods demonstrates the need for an assessment of error under these varying circumstances. Characterization of the applicable background noise will help to ensure that thresholds are reliably set for detection of true MSVs.

Community structure and concordance patterns among zooplankton life stages in subtropical temporary ponds

In this study, we assessed the community structure (species richness and composition) and examined concordance patterns between the active and dormant life stages of the zooplankton (Rotifera, Cladocera and Copepoda) in Southern Brazilian temporary ponds. We also examined pairwise concordance patterns in the species richness and composition between each taxonomic group. We recorded 77 species in the study area. Active communities had higher species richness and a higher number of exclusive species compared to the dormant community. Low concordance was observed in the species richness and composition of the active and dormant communities. Significant patterns were detected between similar life stages of zooplankton taxonomic groups. We found significant concordance between the species richness of dormant stages of Cladocera and Rotifera, and between the active stages of Cladocera and Copepoda. We also detected significant concordant patterns in the similarity for composition of the active stages of Cladocera and Copepoda, and of Rotifera and Copepoda. The lack of concordance between life stages indicates that the dormant communities are not adequate surrogates of the overall diversity of the zooplankton in Southern Brazilian temporary wetlands, at least under similar experimental incubation conditions. However, there is initial evidence that cladocerans and copepods can be employed as surrogates of other zooplankton groups, if the conclusions are strictly limited to active stages of the community.

Clinical Decision Support for Ovarian Carcinoma Subtype Classification: A Pilot Observer Study With Pathology Trainees.

Clinical decision support (CDS) systems could assist less experienced pathologists with certain diagnostic tasks for which subspecialty training or extensive experience is typically needed. The effect of decision support on pathologist performance for such diagnostic tasks has not been examined. To examine the impact of a CDS tool for the classification of ovarian carcinoma subtypes by pathology trainees in a pilot observer study using digital pathology. Histologic review on 90 whole slide images from 75 ovarian cancer patients was conducted by 6 pathology residents using: (1) unaided review of whole slide images, and (2) aided review, where in addition to whole slide images observers used a CDS tool that provided information about the presence of 8 histologic features important for subtype classification that were identified previously by an expert in gynecologic pathology. The reference standard of ovarian subtype consisted of majority consensus from a panel of 3 gynecologic pathology experts. Aided review improved pairwise concordance with the reference standard for 5 of 6 observers by 3.3% to 17.8% (for 2 observers, increase was statistically significant) and mean interobserver agreement by 9.2% (not statistically significant). Observers benefited the most when the CDS tool prompted them to look for missed histologic features that were definitive for a certain subtype. Observer performance varied widely across cases with unanimous and nonunanimous reference classification, supporting the need for balancing data sets in terms of case difficulty. Findings showed the potential of CDS systems to close the knowledge gap between pathologists for complex diagnostic tasks.