Jason M. Baron

Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis

Canonical chromosomal translocations juxtaposing antigen receptor genes and oncogenes are a hallmark of many lymphoid malignancies. These translocations frequently form through the joining of DNA ends from double-strand breaks (DSBs) generated by the recombinase activating gene (RAG)-1 and -2 proteins at lymphocyte antigen receptor loci and breakpoint targets near oncogenes. Our understanding of chromosomal breakpoint target selection comes primarily from the analyses of these lesions, which are selected based on their transforming properties. RAG DSBs are rarely resolved aberrantly in wild-type developing lymphocytes. However, in ataxia telangiectasia mutated (ATM)-deficient lymphocytes, RAG breaks are frequently joined aberrantly, forming chromosomal lesions such as translocations that predispose (ATM)-deficient mice and humans to the development of lymphoid malignancies. Here, an approach that minimizes selection biases is used to isolate a large cohort of breakpoint targets of aberrantly resolved RAG DSBs in Atm-deficient lymphocytes. Analyses of this cohort revealed that frequently, the breakpoint targets for aberrantly resolved RAG breaks are other DSBs. Moreover, these nonselected lesions exhibit a bias for using breakpoints in cis, forming small chromosomal deletions, rather than breakpoints in trans, forming chromosomal translocations.

Computerized provider order entry in the clinical laboratory.

Clinicians have traditionally ordered laboratory tests using paper-based orders and requisitions. However, paper orders are becoming increasingly incompatible with the complexities, challenges, and resource constraints of our modern healthcare systems and are being replaced by electronic order entry systems. Electronic systems that allow direct provider input of diagnostic testing or medication orders into a computer system are known as Computerized Provider Order Entry (CPOE) systems. Adoption of laboratory CPOE systems may offer institutions many benefits, including reduced test turnaround time, improved test utilization, and better adherence to practice guidelines. In this review, we outline the functionality of various CPOE implementations, review the reported benefits, and discuss strategies for using CPOE to improve the test ordering process. Further, we discuss barriers to the implementation of CPOE systems that have prevented their more widespread adoption.

Implementation of Point-of-Care Testing in an Ambulatory Practice of an Academic Medical Center

OBJECTIVES Point-of-care laboratory testing (POCT) offers reduced turnaround time and may promote improved operational efficiency. Few studies have been reported that document improvements from implementing POCT in primary care. METHODS We measured metrics of practice efficiency in a primary care practice before and after implementation of POCT, including the total number of tests ordered, letters and phone calls to patients, and revisits due to abnormal test results. We performed a cost and revenue analysis. RESULTS Following implementation of POCT, there was a 21% decrease in tests ordered per patient (P < .0001); a decrease in follow-up phone calls and letters by 89% and 85%, respectively (P < .0001 and P < .0001); and a 61% decrease in patient revisits (P = .0002). Estimated testing revenues exceeded expenses by

Collateral damage from antigen receptor gene diversification.

6.62 per patient, and potential cost savings from improved efficiency were

Evaluation of the i-STAT point-of-care capillary whole blood prothrombin time and international normalized ratio: comparison to the Tcoag MDAII coagulation analyzer in the central laboratory.

24.64 per patient. CONCLUSIONS POCT can significantly improve clinical operations with cost reductions through improved practice efficiency.

Measurement of high-sensitivity troponin T in noncardiac medical intensive care unit patients. Correlation to mortality and length of stay.

Chromosomal translocations that juxtapose antigen receptor genes and oncogenes are frequently associated with lymphoid malignancies. In this issue, Robbiani et al. (2008) show that activation-induced deaminase (AID), an enzyme involved in antigen receptor gene diversification, generates DNA double-strand breaks (DSBs) in oncogenes, and Tsai et al. (2008) propose that AID and the recombinase-activating gene (RAG) endonuclease may collaborate to generate off-target DSBs.

Using Machine Learning to Predict Laboratory Test Results

BACKGROUND Point-of-care devices for performing a prothrombin time/international normalized ratio (PT/INR) using capillary blood samples are being increasingly used to monitor patients receiving anticoagulation therapy. However, the performance of some devices has been shown to be suboptimal and there are only limited published data comparing specific devices to various central laboratory coagulation analyzers. We report an evaluation of the iSTAT PT/INR with a comparison to the Tcoag MDA II analyzer. METHODS We obtained simultaneous capillary/venous samples on 20 healthy volunteers for a normal range study and on 50 anticoagulated patients for a clinical evaluation. Testing was performed by phlebotomists. We also obtained 68 near simultaneous capillary/venous test results for assessment of performance by non-laboratory personnel. The criteria for determining clinical equivalence of the iSTAT to the MDA II were (1) same clinical category (subtherapeutic INR<2, therapeutic INR 2-3, and supratherapeutic INR>3) or (2) paired values within ≤ 0.4 INR. RESULTS Forty nine of 50 patient sample pairs collected by phlebotomists showed acceptable clinical agreement. Sixty one (61) of 68 patient sample pairs collected by nurses showed acceptable agreement. In all discordant cases the differences were minor and would have resulted in either no or minimal change in therapy. CONCLUSIONS The iSTAT PT/INR compares well to the MDA II when performed by phlebotomists or nurses.

The 2013 symposium on pathology data integration and clinical decision support and the current state of field.

OBJECTIVES To assess the frequency, magnitude, and prognostic significance of elevations in cardiac troponin T in noncardiac critically ill patients, including elevations at levels below the limit of detection of traditional assays. METHODS Using a high-sensitivity assay, we measured troponin T (high-sensitivity troponin T [hsTnT]) in 451 unique patients within 12 hours of their admission to a noncardiac medical intensive care unit. Outcomes of patients, grouped by hsTnT level, were compared. RESULTS Overall, 98% of the study patients had detectable levels of hsTnT (>3 ng/L), and 33% had levels above the diagnostic cutoff of a traditional fourth-generation cardiac troponin T assay. Patient groups with higher hsTnT levels had markedly higher rates of in-hospital mortality (P < .001) and longer stays in the hospital and intensive care unit (P < .01). CONCLUSIONS In noncardiac critically ill patients, cardiac troponin T elevations are common but often at levels undetectable by traditional assays. hsTnT elevations predict a more complex clinical course and an increased risk of death.

A core curriculum for clinical fellowship training in pathology informatics

OBJECTIVES While clinical laboratories report most test results as individual numbers, findings, or observations, clinical diagnosis usually relies on the results of multiple tests. Clinical decision support that integrates multiple elements of laboratory data could be highly useful in enhancing laboratory diagnosis. METHODS Using the analyte ferritin in a proof of concept, we extracted clinical laboratory data from patient testing and applied a variety of machine-learning algorithms to predict ferritin test results using the results from other tests. We compared predicted with measured results and reviewed selected cases to assess the clinical value of predicted ferritin. RESULTS We show that patient demographics and results of other laboratory tests can discriminate normal from abnormal ferritin results with a high degree of accuracy (area under the curve as high as 0.97, held-out test data). Case review indicated that predicted ferritin results may sometimes better reflect underlying iron status than measured ferritin. CONCLUSIONS These findings highlight the substantial informational redundancy present in patient test results and offer a potential foundation for a novel type of clinical decision support aimed at integrating, interpreting, and enhancing the diagnostic value of multianalyte sets of clinical laboratory test results.

Protein C assay performance: an analysis of North American specialized coagulation laboratory association proficiency testing results.

Background: Pathologists and informaticians are becoming increasingly interested in electronic clinical decision support for pathology, laboratory medicine and clinical diagnosis. Improved decision support may optimize laboratory test selection, improve test result interpretation and permit the extraction of enhanced diagnostic information from existing laboratory data. Nonetheless, the field of pathology decision support is still developing. To facilitate the exchange of ideas and preliminary studies, we convened a symposium entitled: Pathology data integration and clinical decision support. Methods: The symposium was held at the Massachusetts General Hospital, on May 10, 2013. Participants were selected to represent diverse backgrounds and interests and were from nine different institutions in eight different states. Results: The day included 16 plenary talks and three panel discussions, together covering four broad areas. Summaries of each presentation are included in this manuscript. Conclusions: A number of recurrent themes emerged from the symposium. Among the most pervasive was the dichotomy between diagnostic data and diagnostic information, including the opportunities that laboratories may have to use electronic systems and algorithms to convert the data they generate into more useful information. Differences between human talents and computer abilities were described; well-designed symbioses between humans and computers may ultimately optimize diagnosis. Another key theme related to the unique needs and challenges in providing decision support for genomics and other emerging diagnostic modalities. Finally, many talks relayed how the barriers to bringing decision support toward reality are primarily personnel, political, infrastructural and administrative challenges rather than technological limitations.