Development of a Diagnostic Test Set to Assess Agreement in Breast Pathology: Practical Application of the Guidelines for Reporting Reliability and Agreement Studies (GRRAS)

Diagnostic test sets are a valuable research tool that contributes importantly to the validity and reliability of studies that assess agreement in breast pathology. In order to fully understand the strengths and weaknesses of any agreement and reliability study, however, the methods should be fully reported. In this paper we provide a step-by-step description of the methods used to create four complex test sets for a study of diagnostic agreement among pathologists interpreting breast biopsy specimens. We use the newly developed Guidelines for Reporting Reliability and Agreement Studies (GRRAS) as a basis to report these methods

Surgical implications and variability in the use of the flat epithelial atypia diagnosis on breast biopsy specimens.

OBJECTIVES: Flat epithelial atypia (FEA) is a relatively new diagnostic term with uncertain clinical significance for surgical management. Any implied risk of invasive breast cancer associated with FEA is contingent upon diagnostic reproducibility, yet little is known regarding its use. MATERIALS AND METHODS: Pathologists in the Breast Pathology Study interpreted one of four 60-case test sets, one slide per case, constructed from 240 breast biopsy specimens. An electronic data form with standardized diagnostic categories was used; participants were instructed to indicate all diagnoses present. We assessed participants\u27 use of FEA as a diagnostic term within: 1) each test set; 2) 72 cases classified by reference as benign without FEA; and 3) six cases classified by reference as FEA. 115 pathologists participated, providing 6900 total independent assessments. RESULTS: Notation of FEA ranged from 0% to 35% of the cases interpreted, with most pathologists noting FEA on 4 or more test cases. At least one participant noted FEA in 34 of the 72 benign non-FEA cases. For the 6 reference FEA cases, participant agreement with the case reference FEA diagnosis ranged from 17% to 52%; diagnoses noted by participating pathologists for these FEA cases included columnar cell hyperplasia, usual ductal hyperplasia, atypical lobular hyperplasia, and atypical ductal hyperplasia. CONCLUSIONS: We observed wide variation in the diagnosis of FEA among U.S. pathologists. This suggests that perceptions of diagnostic criteria and any implied risk associated with FEA may also vary. Surgical excision following a core biopsy diagnosis of FEA should be reconsidered and studied further

Characteristics associated with requests by pathologists for second opinions on breast biopsies.

AIMS: Second opinions in pathology improve patient safety by reducing diagnostic errors, leading to more appropriate clinical treatment decisions. Little objective data are available regarding the factors triggering a request for second opinion despite second opinion consultations being part of the diagnostic system of pathology. Therefore we sought to assess breast biopsy cases and interpreting pathologists characteristics associated with second opinion requests. METHODS: Collected pathologist surveys and their interpretations of 60 test set cases were used to explore the relationships between case characteristics, pathologist characteristics and case perceptions, and requests for second opinions. Data were evaluated by logistic regression and generalised estimating equations. RESULTS: 115 pathologists provided 6900 assessments; pathologists requested second opinions on 70% (4827/6900) of their assessments 36% (1731/4827) of these would not have been required by policy. All associations between case characteristics and requesting second opinions were statistically significant, including diagnostic category, breast density, biopsy type, and number of diagnoses noted per case. Exclusive of institutional policies, pathologists wanted second opinions most frequently for atypia (66%) and least frequently for invasive cancer (20%). Second opinion rates were higher when the pathologist had lower assessment confidence, in cases with higher perceived difficulty, and cases with borderline diagnoses. CONCLUSIONS: Pathologists request second opinions for challenging cases, particularly those with atypia, high breast density, core needle biopsies, or many co-existing diagnoses. Further studies should evaluate whether the case characteristics identified in this study could be used as clinical criteria to prompt system-level strategies for mandating second opinions

Missed visits and mortality among patients establishing initial outpatient HIV treatment

BACKGROUND: Dramatic increases in the number of patients requiring linkage to treatment for human immunodeficiency virus (HIV) infection are anticipated in response to updated Centers for Disease Control and Prevention HIV testing recommendations that advocate routine, opt-out HIV testing. METHODS: A retrospective analysis nested within a prospective HIV clinical cohort study evaluated patients who established initial outpatient treatment for HIV infection at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic from 1 January 2000 through 31 December 2005. Survival methods were used to evaluate the impact of missed visits during the first year of care on subsequent mortality in the context of other baseline sociodemographic, psychosocial, and clinical factors. Mortality was ascertained by query of the Social Security Death Index as of 1 August 2007. RESULTS: Among 543 study participants initiating outpatient care for HIV infection, 60% missed a visit within the first year. The mortality rate was 2.3 deaths per 100 person-years for patients who missed visits, compared with 1.0 deaths per 100 person-years for those who attended all scheduled appointments during the first year after establishing outpatient treatment (P = .02). In Cox proportional hazards analysis, higher hazards of death were independently associated with missed visits (hazard ratio, 2.90; 95% confidence interval, 1.28-6.56), older age (hazard ratio, 1.58 per 10 years of age; 95% confidence interval, 1.12-2.22), and baseline CD4+ cell count \u3c 200 cells/mm(3) (hazard ratio, 2.70; 95% confidence interval, 1.00-7.30). CONCLUSIONS: Patients who missed visits within the first year after initiating outpatient treatment for HIV infection had more than twice the rate of long-term mortality, compared with those patients who attended all scheduled appointments. We posit that early missed visits are not causally responsible for the higher observed mortality but, rather, identify those patients who are more likely to exhibit health behaviors that portend increased subsequent mortality

Functional magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders

A comprehensive neuropsychological/psychiatric, MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The four study groups included: 1. FAS/Partial FAS; 2. Static Encephalopathy/Alcohol Exposed (SE/AE); 3. Neurobehavioral Disorder/Alcohol Exposed (ND/AE); and 4. healthy peers with no prenatal alcohol exposure. fMRI outcomes are reported here. The neuropsychological/psychiatric, MRI, and MRS outcomes are reported separately. fMRI was used to assess activation in seven brain regions during performance of N-back working memory tasks. Children across the full spectrum of FASD exhibited significant working memory deficits and altered activation patterns in brain regions that are known to be involved in working memory. These results demonstrate the potential research and diagnostic value of this non-invasive MR tool in the field of FASD

A Randomized Study Comparing Digital Imaging to Traditional Glass Slide Microscopy for Breast Biopsy and Cancer Diagnosis.

BACKGROUND: Digital whole slide imaging may be useful for obtaining second opinions and is used in many countries. However, the U.S. Food and Drug Administration requires verification studies. METHODS: Pathologists were randomized to interpret one of four sets of breast biopsy cases during two phases, separated by ≥9 months, using glass slides or digital format (sixty cases per set, one slide per case, RESULTS: Sixty-five percent of responding pathologists were eligible, and 252 consented to randomization; 208 completed Phase I (115 glass, 93 digital); and 172 completed Phase II (86 glass, 86 digital). Accuracy was slightly higher using glass compared to digital format and varied by category: invasive carcinoma, 96% versus 93% ( CONCLUSIONS: In this large randomized study, digital format interpretations were similar to glass slide interpretations of benign and invasive cancer cases. However, cases in the middle of the spectrum, where more inherent variability exists, may be more problematic in digital format. Future studies evaluating the effect these findings exert on clinical practice and patient outcomes are required

The FLASH pilot survey: an HI absorption search against MRC 1-Jy radio sources

We report an ASKAP search for associated HI 21-cm absorption against bright radio sources from the Molonglo Reference Catalogue (MRC) 1-Jy sample. The search uses pilot survey data from the ASKAP First Large Absorption Survey in \hi (FLASH) covering the redshift range $0.42 < z < 1.00$. From a sample of 62 MRC 1-Jy radio galaxies and quasars in this redshift range we report three new detections of associated HI 21-cm absorption, yielding an overall detection fraction of $1.8\%^{+4.0\%}_{-1.5\%}$. The detected systems comprise two radio galaxies (MRC 2216$-$281 at $z=0.657$ and MRC 0531$-$237 at $z=0.851$) and one quasar (MRC 2156$-$245 at $z=0.862$). The MRC 0531$-$237 absorption system is the strongest found to date, with a velocity integrated optical depth of $\rm 143.8 \pm 0.4 \ km \ s^{-1}$. All three objects with detected HI 21-cm absorption are peaked-spectrum or compact steep-spectrum (CSS) radio sources, classified based on our SED fits to the spectra. Two of them show strong interplanetary scintillation at 162 MHz, implying that the radio continuum source is smaller than 1 arcsec in size even at low frequencies. Among the class of peaked-spectrum and compact steep-spectrum radio sources, the HI detection fraction is $23\%^{+22\%}_{-13\%}$. This is consistent within $1\sigma$ with a detection fraction of $\approx 42\%^{+21\%}_{-15\%}$ in earlier reported GPS and CSS samples at intermediate redshifts ($0.4 < z < 1.0$). All three detections have a high 1.4 GHz radio luminosity, with MRC 0531$-$237 and MRC 2216$-$281 having the highest values in the sample, $\rm > 27.5 \ W \ Hz^{-1}$. The preponderance of extended radio sources in our sample could partially explain the overall low detection fraction, while the effects of a redshift evolution in gas properties and AGN UV luminosity on the neutral gas absorption still need to be investigated.Comment: 28 pages, 9 figures and 7 Tables. Submitted to MNRA

The molecular basis of breast cancer pathological phenotypes

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or RPPA subtype. Marked nuclear pleomorphism, necrosis, inflammation and high mitotic count were associated with Basal-like subtype and have similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed using the METABRIC dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of epithelial tubule formation was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast