1. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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2. |
- Szatmari, Peter, et al.
(författare)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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3. |
- Bayani, Jane, et al.
(författare)
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Evaluation of multiple transcriptomic gene risk signatures in male breast cancer
- 2021
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Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these tests in male BCa. Here we present the gene expression results of 381 M0, ER+ve, HER2-ve male BCa patients enrolled in the Part 1 (retrospective analysis) of the International Male Breast Cancer Program. Using a custom NanoString™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDX®, and MammaPrint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by us previously. We also examined the prognostic value of other risk scores such as the Genomic Grade Index (GGI), IHC4-mRNA and our prognostic 95-gene signature. In this sample set of male BCa, we demonstrated prognostic utility on univariate analysis. Across all signatures, patients whose samples were identified as low-risk experienced better outcomes than intermediate-risk, with those classed as high risk experiencing the poorest outcomes. As seen with female BCa, the concordance between tests was poor, with C-index values ranging from 40.3% to 78.2% and Kappa values ranging from 0.17 to 0.58. To our knowledge, this is the largest study of male breast cancers assayed to generate risk scores of the current commercial and academic risk tests demonstrating comparable clinical utility to female BCa.
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4. |
- Gonzalez-Ericsson, Paula, et al.
(författare)
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The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers into breast cancer clinical trials and daily practice
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 250:5, s. 667-684
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Forskningsöversikt (refereegranskat)abstract
- Immune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC.
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5. |
- Abazov, V. M., et al.
(författare)
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Search for first generation leptoquark pair production in the electron plus missing energy plus jets final state
- 2011
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 84:7, s. 071104-
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Tidskriftsartikel (refereegranskat)abstract
- We present a search for the pair production of first generation scalar leptoquarks (LQ) in data corresponding to an integrated luminosity of 5.4 fb(-1) collected with the D0 detector at the Fermilab Tevatron Collider in p (p) over bar collisions at root s = 1.96 TeV. In the channel LQLQ -> eqv(e)q', where q, q' are u or d quarks, no significant excess of data over background is observed, and we set a 95% C. L. lower limit of 326 GeV on the LQ mass, assuming equal probabilities of LQ decays to eq and v(e)q'.
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7. |
- Alonso, Jordi, et al.
(författare)
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The case for an international patient-reported outcomes measurement information system (PROMIS®) initiative.
- 2013
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Ingår i: Health and quality of life outcomes. - : Springer Science and Business Media LLC. - 1477-7525. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Patient-reported outcomes (PROs) play an increasingly important role in clinical practice and research. Modern psychometric methods such as item response theory (IRT) enable the creation of item banks that support fixed-length forms as well as computerized adaptive testing (CAT), often resulting in improved measurement precision and responsiveness. Here we describe and discuss the case for developing an international core set of PROs building from the US PROMIS® network.PROMIS is a U.S.-based cooperative group of research sites and centers of excellence convened to develop and standardize PRO measures across studies and settings. If extended to a global collaboration, PROMIS has the potential to transform PRO measurement by creating a shared, unifying terminology and metric for reporting of common symptoms and functional life domains. Extending a common set of standardized PRO measures to the international community offers great potential for improving patient-centered research, clinical trials reporting, population monitoring, and health care worldwide. Benefits of such standardization include the possibility of: international syntheses (such as meta-analyses) of research findings; international population monitoring and policy development; health services administrators and planners access to relevant information on the populations they serve; better assessment and monitoring of patients by providers; and improved shared decision making.The goal of the current PROMIS International initiative is to ensure that item banks are translated and culturally adapted for use in adults and children in as many countries as possible. The process includes 3 key steps: translation/cultural adaptation, calibration, and validation. A universal translation, an approach focusing on commonalities, rather than differences across versions developed in regions or countries speaking the same language, is proposed to ensure conceptual equivalence for all items. International item calibration using nationally representative samples of adults and children within countries is essential to demonstrate that all items possess expected strong measurement properties. Finally, it is important to demonstrate that the PROMIS measures are valid, reliable and responsive to change when used in an international context.IRT item banking will allow for tailoring within countries and facilitate growth and evolution of PROs through contributions from the international measurement community. A number of opportunities and challenges of international development of PROs item banks are discussed.
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8. |
- Bagge, Roger Olofsson, et al.
(författare)
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Population-Based Validation of the MIA and MSKCC Tools for Predicting Sentinel Lymph Node Status
- 2024
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Ingår i: JAMA Surgery. - : AMER MEDICAL ASSOC. - 2168-6254 .- 2168-6262.
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Tidskriftsartikel (refereegranskat)abstract
- Importance Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested.Objective To determine the clinical utility of the MIA and MSKCC models.Design, Setting, and Participants This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023.Main Outcomes and Measures, The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm(2) and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients.Results Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms led to a net reduction of 8 avoidable SLNBs per 100 patients for the MSKCC nomogram and 7 per 100 patients for the limited MIA nomogram compared to a strategy of SLNB for all.Conclusions and Relevance This study confirmed the statistical performance of both the MSKCC and limited MIA models in a large, nationally representative data set. However, decision curve analysis demonstrated that using the models only improved selection for SLNB compared to biopsy in all patients when a risk threshold of at least 7% was used, with the greatest benefit seen for T2 melanomas at a threshold of 10%. Care should be taken when using these nomograms to guide selection for SLNB at the lowest thresholds.
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9. |
- Bekes, Katrin, et al.
(författare)
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Pediatric patients' reasons for visiting dentists in all WHO regions
- 2021
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Ingår i: Health and Quality of Life Outcomes. - : BioMed Central (BMC). - 1477-7525. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact are the four oral health-related quality of life (OHRQoL) dimensions (4D) or areas in which oral disorders impact pediatric patients. Using their dentists' assessment, the study aimed to evaluate whether pediatric dental patients' oral health concerns fit into the 4D of the Oral Health-Related Quality of Life (OHRQoL) construct.METHODS: Dentists who treat children from 32 countries and all WHO regions were selected from a web-based survey of 1580 international dentists. Dentists were asked if their pediatric patients with current or future oral health concerns fit into the 4D of the Oral Health-Related Quality of Life (OHRQoL) construct. Proportions of all pediatric patients' oral health problems and prevention needs were computed.FINDINGS: Data from 101 dentists treating children only and 523 dentists treating children and adults were included. For 90% of pediatric patients, their current oral health problems fit well in the four OHRQoL dimensions. For 91% of oral health problems they intended to prevent in the future were related to these dimensions as well. Both numbers increased to at least 96% when experts analyzed dentists´ explanations of why some oral health problems would not fit these four categories.CONCLUSIONS: The study revealed the four fundamental components of dental patients, i.e., the four OHRQoL dimensions (Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact) are also applicable for pediatric patients, regardless of whether they have current or future oral health concerns, and should be considered when measuring OHRQoL in the pediatric dental patient population.
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10. |
- Bettegowda, Chetan, et al.
(författare)
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Detection of circulating tumor DNA in early- and late-stage human malignancies
- 2014
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:224, s. 224ra24-
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Tidskriftsartikel (refereegranskat)abstract
- The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
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