Generating Clinical-Grade Gene-Disease Validity Classifications Through the ClinGen Data Platforms.

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the standardization, harmonization, and dissemination of Gene-Disease Validity data through the creation of frameworks and the utilization of common data standards. This infrastructure is based on several applications, including the ClinGen GeneTracker, Gene Curation Interface, Data Exchange, GeneGraph, and website.

Factors associated with short-term hospital readmission rates for breast cancer patients in Western Australia: an observational study.

BACKGROUND: Unplanned hospital readmissions after surgical treatment for breast cancer are an indicator of morbidity. We explore the relationship between the rate of unplanned hospital readmissions within 42 days of initial treatment and various factors, including tumor size and histology, lymph node involvement, type of surgical treatment, mastectomy, or breast-conserving surgery, and patient demographics. METHODS: Linked Western Australian cancer mortality and hospital morbidity data were used in the assessment of readmissions within a period of 42 days after initial surgical treatment for breast cancer. Planned admissions for adjuvant treatment such as chemotherapy or radiotherapy were deleted. Survival models for multiple events per subject were applied to analyze the data. RESULTS: The analysis reveals that patients more likely to experience lower recurrence of short-term unplanned hospital readmissions include those with smaller tumors, private insurance, and who reside in metropolitan areas. The model also includes important two-way interaction terms involving tumor histology, area of residence, and surgical treatment, and between lymph node involvement and patient age. CONCLUSIONS: This study suggests that the choice of breast-conserving surgery as a treatment for breast cancer does not invariably result in better postoperative morbidity, but rather, that other factors, including tumor size and patient demographics, play a critical role in the short term. These results differ from a previous study of longterm hospital readmissions-country of birth and method of payment were found to be associated with short-term hospital admission but not with longterm readmissions.

Retracted: Factors affecting hospital readmission rates for breast cancer patients in Western Australia.

By this notice, the Editor and the Publisher of the Journal of Surgical Oncology retract from publication the following article: "Factors Affecting Hospital Readmission Rates for Breast Cancer Patients in Western Australia," Michael A. Martin, Ramona Meyricke, Terry O'Neill, and Steven Roberts, Journal of Surgical Oncology, Published online January 17, 2007, DOI: 10.1002/jso.20742. The article has been formally deemed a duplicate submission. The Editor and the Publisher of the Journal of Surgical Oncology regret the occurrence of this unfortunate incident.

Tape Lift Sampling of Chemical Threat Agents.

Commercial-off-the-shelf (COTS) materials were evaluated as surface samplers for the Department of Homeland Security Chemical Forensics Program. The program helps evidence collectors identify trace chemical residues at incident scenes. COTS items are widely available, produced in large lots, and with strict controls. Chemical attribution signatures were collected from common surfaces. Eight tape lift candidates were considered, five were chosen based on performance and tested for analytical interferences and extraction efficiencies with 14 chemicals. Three products (duct tape, print lifters, command strips) were evaluated for uptake from common interior surfaces (glass, tile, ABS plastic). Duct tape provided highest recoveries across all surfaces. Even the most volatile analytes were detected in the ABS plastic samples (nondetections in others), regardless of tape lift material used. The porous plastic substrate provides better target retention than glass and tile surfaces. Forensic field operators should sample surfaces made of ABS plastic (keyboards, remotes, phones, etc.) whenever possible.

Mastectomy or breast conserving surgery? Factors affecting type of surgical treatment for breast cancer--a classification tree approach.

BACKGROUND: A critical choice facing breast cancer patients is which surgical treatment--mastectomy or breast conserving surgery (BCS)--is most appropriate. Several studies have investigated factors that impact the type of surgery chosen, identifying features such as place of residence, age at diagnosis, tumor size, socio-economic and racial/ethnic elements as relevant. Such assessment of "propensity" is important in understanding issues such as a reported under-utilisation of BCS among women for whom such treatment was not contraindicated. Using Western Australian (WA) data, we further examine the factors associated with the type of surgical treatment for breast cancer using a classification tree approach. This approach deals naturally with complicated interactions between factors, and so allows flexible and interpretable models for treatment choice to be built that add to the current understanding of this complex decision process. METHODS: Data was extracted from the WA Cancer Registry on women diagnosed with breast cancer in WA from 1990 to 2000. Subjects' treatment preferences were predicted from covariates using both classification trees and logistic regression. RESULTS: Tumor size was the primary determinant of patient choice, subjects with tumors smaller than 20 mm in diameter preferring BCS. For subjects with tumors greater than 20 mm in diameter factors such as patient age, nodal status, and tumor histology become relevant as predictors of patient choice. CONCLUSION: Classification trees perform as well as logistic regression for predicting patient choice, but are much easier to interpret for clinical use. The selected tree can inform clinicians' advice to patients.

Predictive value of BMD for hip and other fractures.

UNLABELLED: The relationship between BMD and fracture risk was estimated in a meta-analysis of data from 12 cohort studies of approximately 39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score. INTRODUCTION: The aim of this study was to quantify the relationship between BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value. MATERIALS AND METHODS: We studied 9891 men and 29,082 women from 12 cohorts comprising EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and 2 cohorts from Gothenburg. Cohorts were followed for up to 16.3 years and a total of 168,366 person-years. The effect of BMD on fracture risk was examined using a Poisson model in each cohort and each sex separately. Results of the different studies were then merged using weighted coefficients. RESULTS: BMD measurement at the femoral neck with DXA was a strong predictor of hip fractures both in men and women with a similar predictive ability. At the age of 65 years, risk ratio increased by 2.94 (95% CI = 2.02-4.27) in men and by 2.88 (95% CI = 2.31-3.59) in women for each SD decrease in BMD. However, the effect was dependent on age, with a significantly higher gradient of risk at age 50 years than at age 80 years. Although the gradient of hip fracture risk decreased with age, the absolute risk still rose markedly with age. For any fracture and for any osteoporotic fracture, the gradient of risk was lower than for hip fractures. At the age of 65 years, the risk of osteoporotic fractures increased in men by 1.41 per SD decrease in BMD (95% CI = 1.33-1.51) and in women by 1.38 per SD (95% CI = 1.28-1.48). In contrast with hip fracture risk, the gradient of risk increased with age. For the prediction of any osteoporotic fracture (and any fracture), there was a higher gradient of risk the lower the BMD. At a z score of -4 SD, the risk gradient was 2.10 per SD (95% CI = 1.63-2.71) and at a z score of -1 SD, the risk was 1.73 per SD (95% CI = 1.59-1.89) in men and women combined. A similar but less pronounced and nonsignificant effect was observed for hip fractures. Data for ultrasound and peripheral measurements were available from three cohorts. The predictive ability of these devices was somewhat less than that of DXA measurements at the femoral neck by age, sex, and BMD value. CONCLUSIONS: We conclude that BMD is a risk factor for fracture of substantial importance and is similar in both sexes. Its validation on an international basis permits its use in case finding strategies. Its use should, however, take account of the variations in predictive value with age and BMD.

A rapid cleanup method for the isolation and concentration of pyrrolizidine alkaloids in comfrey root.

Preparations from comfrey (Symphytum officinale and S. x uplandicum) root and leaf contain varying levels of the hepatotoxic pyrrolizidine alkaloids (PAs). Reference compounds for comfrey are not commercially available, and there is currently no rapid extraction or analytical method capable of determining low levels in raw materials or as adulterants in commercially available extracts. A solid-phase extraction (SPE) method was developed using an Ergosil cleanup column that specifically binds the PAs. With this method, powdered comfrey root was extracted by sonication and shaking with basic chloroform. The extract was applied to the cleanup column under vacuum, washed with 2 mL acetone-chloroform (8 + 2, v/v) followed by 2 mL petroleum ether to remove excess chloroform. The column was dried under vacuum, and the PAs were eluted with 2 successive 1 mL aliquots methanol. Percent recoveries of the PAs following Ergosil SPE had an overall average of 96.8%, with RSD of 3.8% over a range of 1.0 to 25.0 g extracted in 100 mL. Average precision of the method (n = 3 over 4 extraction concentrations) gave an overall RSD of 6.0% for the 5 alkaloids, with a range of 0.8% (5 g in 100 mL) to 11.2% (25 g in 100 mL). Recovery optimization testing showed that 1.0 g comfrey root extracted in 100 mL yielded the greatest recovery (% dry weight) of the PAs, with an extraction efficiency and accuracy of 94.2%, and RSD of 1.7% (n = 9). The unique properties of the Ergosil cleanup column provide rapid sample cleanup, volume reduction, and concentration of PAs from comfrey extracts, and allow the eluant to be analyzed directly by traditional chromatographic methods.

Sustaining development of stratified medicines in the UK healthcare system: a commentary.

The UK healthcare system holds a favorable position in the development of stratified medicines through strong scientific innovation, robust biotechnology and pharmaceutical industries and comparatively simple regulatory and reimbursement processes. Organizations such as its robust health technology assessment agency, the NICE and its mature socialized healthcare system, the National Health Service, enable innovative medicines, including stratified treatments for cancer and infectious disease, to be rapidly assessed for their effectiveness and value to patients in the UK. However, our recent observations with a variety of UK healthcare stakeholders suggest that certain features need to be improved if the favorable position in stratified medicine development, and consequential beneficial outcome to patients, is to be sustained and indeed further enhanced to a position of pre-eminence. Key changes suggested are removing healthcare silos and enabling multidisciplinary teams to translate scientific and medical innovation into the best practice; expanding the UK skill base in certain disciplines including medical pathology, health economics and clinical informatics; and using successful pilot cases of stratified medicines to better educate stakeholders in a drive to change healthcare culture. Through this cultural change, the UK would offer healthcare based on prediction and prevention rather than symptom-based diagnosis and reactive treatment.

Breast-conserving surgery versus mastectomy for survival from breast cancer: the Western Australian experience.

BACKGROUND: The focus of this study was the relative survival rates of breast cancer patients whose treatment was breast-conserving surgery compared with that of mastectomy, adjusting for tumor size and nodal status because these factors may be intrinsically associated with mastectomy being the treatment of choice. Patient age was also accounted for in the model. By adjusting for these factors, we mitigate them as confounders of treatment choice in assessing effects on survival rates. METHODS: Data were sourced from linked administrative data from the Western Australian Department of Health Record Linkage Unit. The data consisted of linked records containing the diagnosis, subsequent hospital admission, and death records of about 3000 women diagnosed with cancer in Western Australia between 1 January 1995 and 31 December 1999. Cox proportional hazards regression was used to investigate survival outcomes of breast-conserving surgery compared with that of mastectomy, adjusting for tumor size, nodal status, and subject age. RESULTS: The hazard of death is reduced by a factor of about one half for subjects whose treatment was breast-conserving surgery over treatment by mastectomy. Furthermore, the hazard of death increases substantially for subjects with nodal involvement over subjects for whom there has been no identified spread to regional lymph nodes. Hazard of death increases as both age and tumor size increase. CONCLUSIONS: Western Australian breast cancer patients treated with breast-conserving surgery have improved survival outcomes over those treated with mastectomy, after allowing for tumor size, patient age, and lymph node involvement.

Variation in back pain between countries: the example of Britain and Germany.

STUDY DESIGN: Cross-sectional survey with personal interviews. OBJECTIVE: To study national differences in subjective health, back pain, and self-perceived disability between the United Kingdom and Germany. SUMMARY OF BACKGROUND DATA: Back pain is a leading health problem in most Western populations, causing enormous costs to the national health systems. Different prevalence rates were reported from many countries, but rarely as a result of a direct comparison based on an identical study design. METHODS: A total of 6,235 male and female participants 50 to 79 years of age (population-based stratified random samples) were recruited in 6 British and 8 German study centers. The interviewer administered standardized questionnaire included a section about presence and severity of back pain. RESULTS: Past and current back pain was more frequent among German participants and different between East and West German centers. The differences in back pain prevalence rates could not be explained by less favorable risk profiles among German respondents. CONCLUSIONS: Intercultural differences in perceiving or reporting back pain can be hypothesized as the most likely explanation of the markedly different prevalence rates of the disorder in the United Kingdom and East and West Germany.