An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY challenge

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Sedimentology, chemostratigraphy, and stromatolites of lower Paleoproterozoic carbonates, Turee Creek Group, Western Australia

The ca. 2.45–2.22 Ga Turee Creek Group, Western Australia, contains carbonate- rich horizons that postdate earliest Proterozoic iron formations, bracket both Paleoproterozoic glaciogenic beds and the onset of the Great Oxidation Event (GOE), and predate ca. 2.2–2.05 Ga Lomagundi-Jatuli C-isotopic excursion(s). As such, Turee Creek carbonate strata provide an opportunity to characterize early Paleoproterozoic carbonate sedimentation and carbon cycle dynamics in the context of significant global change. Here, we report on the stratigraphy, sedimentology, petrology, carbon isotope chemostratigraphy, and stromatolite development for carbonate-rich successions within the pre-glacial part of the Kungarra Formation and the postglacial Kazput Formation. Kungarra carbonate units largely occur as laterally discontinuous beds within a thick, predominantly siliciclastic shelf deposit. While this succession contains thin microbialite horizons, most carbonates consist of patchy calcite overgrowths within a siliciclastic matrix. C-isotopic values show marked variation along a single horizon and even within hand samples, reflecting spatially and temporally variable mixing between dissolved inorganic carbon in seawater and isotopically light inorganic carbon generated via syn- and post-depositional remineralization of organic matter. In contrast, the Kazput carbonates consist of subtidal stromatolites, grainstones, and micrites deposited on a mixed carbonate-siliciclastic shelf. These carbonates exhibit moderate δ13 C values of -2‰ to +1.5‰ and likely preserve a C-isotopic signature of seawater. Kazput carbonates, thus, provide some of the best available evidence that an interval of unexceptional C-isotopic values separates the Lomagundi-Jatuli C-isotopic excursion(s) from the initiation of the GOE as inferred from multiple sulfur isotopes (loss 4 of mass independent fractionation). The Kazput Formation also contains unusual, m-scale stromatolitic buildups, which are composed of sub-mm laminae and discontinuous, convex upward lenticular precipitates up to a few mm in maximum thickness. Laminae, interpreted as microbial mat layers, contain quartz and clay minerals as well as calcite, whereas precipitate lenses consist of interlocking calcite anhedra, sometimes showing faint mm-scale banding. These cements formed either as infillings of primary voids formed by gas emission within penecontemporaneously lithified mats, or as local seafloor precipitates that formed on, or within, surface mats. It is possible that both mechanisms interacted to form the unique Kazput stromatolites. These microbialites speak to a distinctive interaction between life and environment early in the Paleoproterozoic Era.Earth and Planetary Science

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Cooperating yet distinct brain networks engaged during naturalistic paradigms: A meta-analysis of functional MRI results

Cognitive processes do not occur by pure insertion and instead depend on the full complement of co-occurring mental processes, including perceptual and motor functions. As such, there is limited ecological validity to human neuroimaging experiments that use highly controlled tasks to isolate mental processes of interest. However, a growing literature shows how dynamic, interactive tasks have allowed researchers to study cognition as it more naturally occurs. Collective analysis across such neuroimaging experiments may answer broader questions regarding how naturalistic cognition is biologically distributed throughout the brain. We applied an unbiased, data-driven, meta-analytic approach that uses k-means clustering to identify core brain networks engaged across the naturalistic functional neuroimaging literature. Functional decoding allowed us to, then, delineate how information is distributed between these networks throughout the execution of dynamical cognition in realistic settings. This analysis revealed six recurrent patterns of brain activation, representing sensory, domain-specific, and attentional neural networks that support the cognitive demands of naturalistic paradigms. Though gaps in the literature remain, these results suggest that naturalistic fMRI paradigms recruit a common set of networks that that allow both separate processing of different streams of information and integration of relevant information to enable flexible cognition and complex behavior

Influenza Vaccine Effectiveness Against Antigenically Drifted Influenza Higher Than Expected in Hospitalized Adults: 2014-2015

BACKGROUND: The 2014-2015 influenza season was severe, with circulating influenza A (H3N2) viruses that were antigenically drifted from the vaccine virus. Reported vaccine effectiveness (VE) estimates from ambulatory care settings were markedly decreased. METHODS: Adults, hospitalized at 2 hospitals in southeast Michigan for acute respiratory illnesses, defined by admission diagnoses, of ≤10 days duration were prospectively enrolled. Throat and nasal swab specimens were collected, combined, and tested for influenza by real-time reverse transcription polymerase chain reaction. VE was estimated by comparing the vaccination status of those testing positive for influenza with those testing negative in logistic regression models adjusted for age, sex, hospital, calendar time, time from illness onset to specimen collection, frailty score, and Charlson comorbidity index (CCI). RESULTS: Among 624 patients included in the analysis, 421 (68%) were vaccinated, 337 (54%) were female, 220 (35%) were age ≥65 years, and 92% had CCI \u3e 0, indicating ≥1 comorbid conditions. Ninety-eight (16%) patients tested positive for influenza A (H3N2); among 60 (61%) A (H3N2) viruses tested by pyrosequencing, 53 (88%) belonged to the drifted 3C.2a genetic group. Adjusted VE was 43% (95% confidence interval [CI], 4-67) against influenza A (H3N2); 40% (95% CI, -13 to 68) for those \u3c65 \u3eyears, and 48% (95% CI, -33 to 80) for those ≥65 years. Sensitivity analyses largely supported these estimates. CONCLUSIONS: VE estimates appeared higher than reports from similar studies in ambulatory care settings, suggesting that the 2014-2015 vaccine may have been more effective in preventing severe illness requiring hospitalization