EHR-Driven Delivery of EPA Assessments Significantly Improves Participation.

INTRODUCTION: Digital education tools are a cornerstone in the evolution to CBME through EPAs. Successful implementation requires understanding the variable impacts of EHR-driven delivery of EPAs, flexible digital device access to EPAs, and user-behavior trends. METHODS: Through a HIPAA compliant, flexible-device accessible, surgical education platform, general surgery training programs at 21 institutions collected EPA from July 2023 to April 2024. At 5 EHR-integrated institutions (EHR+), EPA were created for clinical activities based on the OR schedule, automatically pushed to attendings and residents with built in completion reminders. At 16 institutions without EHR integration (EHR-), EPA were initiated manually. To improve user experience, care phases were bundled (cEPA). We compared the EHR+ and EHR- groups, computing descriptive statistics on the cEPAs completed and user behavior metrics. RESULTS: We collected 4187 cEPAs in total, with 82% at EHR+ institutions and 18% at EHR- institutions. Platform triggering dramatically drove cEPA completion for both faculty and residents, 88% and 81%, respectively. Only 3% were initiated by the faculty or resident. Faculty at EHR+ institutions strongly preferred the automated OR-triggered workflow to start their EPAs (Chi-squared test, p ≈ 0). Faculty completed all 3 care phases nearly 80% of the time. Time reminders specifically drive EPA completion for residents and faculty on weekdays and build habits on weekends. 71% of cEPAs completed were by computer, and 29% by phone. More comments were provided when computers were used. Residents reviewed feedback with a median lag of 1 hour and 29 min after results were available. CONCLUSIONS: EHR-driven delivery of EPA leads to a 4.6-fold increase in EPAs completed. EPA initiation is the most critical phase in the workflow and EHR-data driven alerts drive this action. These alerts are also effective drivers of habit formation. Flexible device access is important to increase EPAs completed and improve the usefulness through comments for residents.

Overcoming Systems Factors in Case Logging with Artificial Intelligence Tools.

INTRODUCTION: Case logs are foundational data in surgical education, yet cases are consistently under-reported. Logging behavior is driven by multiple human and systems factors, including time constraints, ease of case data retrieval, access to data-entry tools, and procedural code decision tools. METHODS: We examined case logging trends at three mid-sized, general surgery training programs from September 2016-October 2020, January 2019-October 2020 and May 2019-October 2020, respectively. Across the programs we compared the number of cases logged per week when residents logged directly to ACGME versus via a resident education platform with machine learning-based case logging assistance tools. We examined case logging patterns across 4 consecutive phases: baseline default ACGME logging prior to platform access (P0 "Manual"), full platform logging assistance (P1 "Assisted"), partial platform assistance requiring manual data entry without data integrations (P2 "Notebook"), and resumed fully integrated platform with logging assistance (P3 "Resumed"). RESULTS: 31,385 cases were logged utilizing the platform since 2016 by 171 residents across the 3 programs.Intelligent case logging assistance significantly increased case logging rates, from 1.44 ± 1.48 cases by manual entry in P0 to 4.77 ± 2.45 cases per resident per week via the platform in P1 (p-value < 0.00001). Despite the burden of manual data entry when the platform's data connectivity was paused, the tool helped to increase overall case logging into ACGME to 2.85 ± 2.37 cases per week (p-value = 0.0002). Upon resuming the data connectivity, case logging levels rose to 4.54 ± 3.33 cases per week via the platform, equivalent to P1 levels (insignificant difference, p-value = 0.57). CONCLUSIONS: Mapping the influence of systems and human factors in high-quality case logs allows us to target interventions to continually improve the training of surgical residents. System level factors such as access to alternate automation-drive tools and operative schedule integrated platforms to assist in ACGME case log has a significant impact on the number of cases captured in logs.

The Attending Meritocracy: Implementation of a Novel Team-Based Approach to Provide Effective Resident Feedback.

OBJECTIVE: Providing timely quality feedback is an essential responsibility of teaching faculty and is critical for resident assessment and development throughout training. Numerous evaluation platforms have been created to provide immediate and big picture end-of-rotation feedback. Faculty suffer burnout from electronic documentation demands and workload and as a result, evaluation activity is relegated to a lower priority leading to poor compliance. We implemented a novel team-based Attending Meritocracy (AM)1 program that encompasses monetary, automated reminder, and punitive components, while adding a competition element to further engage faculty. The aim of this study is to determine effectiveness of AM in increasing compliance with resident feedback. DESIGN, SETTING AND PARTICIPANTS: Surgical faculty (n = 36) were divided into 5 teams according to service and subspecialty. Points could be earned by completing surgical (Firefly, MiniCEX) or rotation (New Innovations) evaluations, leaving comments, and other educational tasks. A prize for the highest scoring team was identified as a dinner financed by the non-winning teams. Data from evaluation platforms was extracted. Continuous variables were compared using Mann-Whitney-U test, and categorical variables using chi-squared test. RESULTS: When comparing July 2019 to February 2020 (control period) with July 2020 to February 2021(initial implementation period), we found a 237% increase in submitted NI evaluations (n = 111-374) and a 42.5% decrease in median time to completion from 60.4 (33.2-106.9) days to 34.7 (24.0-64.5) days, (p = 0.001).2 We observed an increase in operative evaluations completed (Mini CEX n = 4-97, Firefly n = 150-1284). CONCLUSIONS: Implementation of a team-based attending meritocracy program is an effective budget neutral method to increase completion of resident evaluations. Further investigation is needed to assess improvement in quality of feedback as well as to explore it's impact on progression of resident autonomy.

Use of a Secure Web-Based Data Management Platform to Track Resident Operative Performance and Program Educational Quality Over Time.

OBJECTIVE: In surgery residency programs, Accreditation Council for Graduate Medical Education mandated performance assessment can include assessment in the operating room to demonstrate that necessary quality and autonomy goals are achieved by the conclusion of training. For the past 3 years, our institution has used The Ottawa Surgical Competency Operating Room Evaluation (O-SCORE) instrument to assess and track operative skills. Evaluation is accomplished in near real-time using a secure web-based platform for data management and analytics (Firefly). Simultaneous to access of the platform's case logging function, the O-SCORE instrument is delivered to faculty members for rapid completion, facilitating quality, and timeliness of feedback. We sought to demonstrate the platform's utility in detecting operative performance changes over time in response to focused educational interventions based on stored case log and O-SCORE data. DESIGN: Stored resident performance assessments for the most frequently performed laparoscopic procedures (cholecystectomy, appendectomy, inguinal hernia repair, ventral hernia repair) were examined for 3 successive academic years (2016-2019). During this time, 4 of 36 residents had received program-assigned supplemental simulation training to improve laparoscopic skills. O-SCORE data for these residents were extracted from peer data, which were used for comparisons. Assigned training consisted of a range of videoscopic and virtual reality skills drills with performance objectives. O-SCORE responses were converted to integers and autonomy scores for items pertaining to technical skill were compared before and after educational interventions (Student's t-tests). These scores were also compared to aggregate scores in the nonintervention group. Bayesian-modeled learning curves were used to characterize patterns of improvement over time. SETTING: University of Massachusetts Medical School-Baystate Surgery Residency and Baystate Medical Center PARTICIPANTS: General surgery residents (n = 36) RESULTS: During the period of review, 3325 resident cases were identified meeting the case type criteria. As expected, overall autonomy increased with the number of cases performed. The 4 residents who had been assigned supplemental training (6-18 months) had preintervention score averages that were lower than that of the nonintervention group (2.25 ± 0.43 vs 3.57 ± 1.02; p < 0.0001). During the respective intervention periods, all 4 residents improved autonomy scores (increase to 3.40 ± 0.61; p < 0.0001). Similar improvements were observed for tissue handling, instrument handling, bimanual dexterity, visuospatial skill, and operative efficiency component skills. Postintervention scores were not significantly different compared to scores for the non-intervention group. Bayesian-modeled learning curves showed a similar pattern of postintervention performance improvement. CONCLUSIONS: The data management platform proved to be an effective tool to track responses to supplemental training that was deemed necessary to close defined skills gaps in laparoscopic surgery. This could be seen both in individual and in aggregated data. We were gratified that at the conclusion of the supplemental training, O-SCORE results for the intervention group were not different than those seen in the non-intervention group.

Education Management Platform Enables Delivery and Comparison of Multiple Evaluation Types.

OBJECTIVE: The purpose of this study was to determine whether an automated platform for evaluation selection and delivery would increase participation from surgical teaching faculty in submitting resident operative performance evaluations. DESIGN: We built a HIPAA-compliant, web-based platform to track resident operative assignments and to link embedded evaluation instruments to procedure type. The platform matched appropriate evaluations to surgeons' scheduled procedures, and delivered multiple evaluation types, including Ottawa Surgical Competency Operating Room Evaluation (O-Score) evaluations and Operative Performance Rating System (OPRS) evaluations. Prompts to complete evaluations were made through a system of automatic electronic notifications. We compared the time spent in the platform to achieve evaluation completion. As a metric for the platform's effect on faculty participation, we considered a task that would typically be infeasible without workflow optimization: the evaluator could choose to complete multiple, complementary evaluations for the same resident in the same case. For those cases with multiple evaluations, correlation was analyzed by Spearman rank test. Evaluation data were compared between PGY levels using repeated measures ANOVA. SETTING: The study took place at 4 general surgery residency programs: The University of Massachusetts Medical School-Baystate, the University of Connecticut School or Medicine, the University of Iowa Carver College of Medicine, and Maimonides Medical Center. PARTICIPANTS: From March 2017 to February 2019, the study included 70 surgical teaching faculty and 101 general surgery residents. RESULTS: Faculty completed 1230 O-Score evaluations and 106 OPRS evaluations. Evaluations were completed quickly, with a median time of 36 ± 18 seconds for O-Score evaluations, and 53 ± 51 seconds for OPRS evaluations. 89% of O-Score and 55% of OPRS evaluations were completed without optional comments within one minute, and 99% of O-Score and 82% of OPRS evaluations were completed within 2 minutes. For cases eligible for both evaluation types, attendings completed both evaluations on 74 of 221 (33%) of these cases. These paired evaluations strongly correlated on resident performance (Spearman coefficient = 0.84, p < 0.00001). Both evaluation types stratified operative skill level by program year (p < 0.00001). CONCLUSIONS: Evaluation initiatives can be hampered by the challenge of making multiple surgical evaluation instruments available when needed for appropriate clinical situations, including specific case types. As a test of the optimized evaluation workflow, and to lay the groundwork for future data-driven design of evaluations, we tested the impact of simultaneously delivering 2 evaluation instruments via a secure web-based education platform. We measured the evaluation completion rates of faculty surgeon evaluators when rating resident operative performance, and how effectively the results of evaluation could be analyzed and compared, taking advantage of a highly integrated management of the evaluative information.

Novel Educational Information Management Platform Improves the Surgical Skill Evaluation Process of Surgical Residents.

OBJECTIVE: We sought to increase compliance and timeliness of surgery resident operative evaluation, by providing faculty and residents with a Platform-linking evaluation to analytics and machine-learning-facilitated case logging. DESIGN: We built a HIPAA-compliant web-based Platform for comprehensive management of resident education information, including resident operative performance evaluations. To assess evaluation timeliness, we compared the lag time for Platform-based evaluations to that of end-of-rotation evaluations. We also assessed evaluation compliance, based on a time threshold of 5 days for Platform evaluations and 2 weeks for end-of-rotation evaluations. SETTING: University of Massachusetts, Baystate Medical Center, General Surgery Residency. PARTICIPANTS: Twenty three attendings and 43 residents for the Platform cohort; 15 services and 45 residents for the end-of-rotation cohort. RESULTS: Three hundred and fifty-eight Platform evaluations were completed by 23 attendings for 43 residents for March through October 2017. Six hundred and ten end-of-rotation evaluations by 15 attendings for 45 residents were used for comparison (September 2015 through June 2017). Of Platform evaluations, 41.3% were completed within 24 hours of the operation (16.5% in 6 hours, 33.3% in 12 hours, and 62.2% in 48 hours), with 24.3% of evaluations completed within 3 hours after e-mail reminders. In the first 6 weeks (March 1 through April 12) 4.5 ± 3.7 evaluations were completed per week compared to 18.8 ± 5.8 in the last (September 18 through October 31). Evaluation lag times improved with the use of the Platform, both for median lag of 35 days earlier (1 ± 1.5 days Platform, 36 ± 28.2 days traditional, p < 0.0001) and a mean lag of 41 days earlier (3.0 ± 4.7 days Platform, 44.0 ± 32.6 days traditional, p < 0.0001). CONCLUSIONS: Our comprehensive Platform facilitated faculty compliance with evaluation requirements and timeliness of availability of performance information (often in near real time) for both residents and residency leadership. The added value of the Platform's integration of evaluations with resident and attending case logging may account for the rapidly increasing number of operative skill evaluations over the short time span since implementation.

Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-Mpl.

Thrombopoietin (Thpo) signaling through the c-Mpl receptor promotes either quiescence or proliferation of hematopoietic stem cells (HSCs) in a concentration-dependent manner; however, in vivo Thpo serum levels are responsive to platelet mass rather than HSC demands, suggesting additional regulation exists. Ott1 (Rbm15), a spliceosomal component originally identified as a fusion partner in t(1;22)-associated acute megakaryocytic leukemia, is also essential for maintaining HSC quiescence under stress. Ott1 controls the alternative splicing of a dominant negative isoform, Mpl-TR, capable of inhibiting HSC engraftment and attenuating Thpo signaling. Ott1, which associates with Hdac3 and the histone methyltransferase, Setd1b, binds to both c-Mpl RNA and chromatin and regulates H4 acetylation and H3K4me3 marks. Histone deacetylase or histone methyltransferase inhibition also increases Mpl-TR levels, suggesting that Ott1 uses an underlying epigenetic mechanism to control alternative splicing of c-Mpl. Manipulation of Ott1-dependent alternative splicing may therefore provide a novel pharmacologic avenue for regulating HSC quiescence and proliferation in response to Thpo.

Antigen availability determines CD8⁺ T cell-dendritic cell interaction kinetics and memory fate decisions.

T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8⁺ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics.

CD28 costimulation regulates genome-wide effects on alternative splicing.

CD28 is the major costimulatory receptor required for activation of naïve T cells, yet CD28 costimulation affects the expression level of surprisingly few genes over those altered by TCR stimulation alone. Alternate splicing of genes adds diversity to the proteome and contributes to tissue-specific regulation of genes. Here we demonstrate that CD28 costimulation leads to major changes in alternative splicing during activation of naïve T cells, beyond the effects of TCR alone. CD28 costimulation affected many more genes through modulation of alternate splicing than by modulation of transcription. Different families of biological processes are over-represented among genes alternatively spliced in response to CD28 costimulation compared to those genes whose transcription is altered, suggesting that alternative splicing regulates distinct biological effects. Moreover, genes dependent upon hnRNPLL, a global regulator of splicing in activated T cells, were enriched in T cells activated through TCR plus CD28 as compared to TCR alone. We show that hnRNPLL expression is dependent on CD28 signaling, providing a mechanism by which CD28 can regulate splicing in T cells and insight into how hnRNPLL can influence signal-induced alternative splicing in T cells. The effects of CD28 on alternative splicing provide a newly appreciated means by which CD28 can regulate T cell responses.

Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress.

Aging degrades hematopoietic stem cell (HSC) functions, including stress response; however, the involved molecular pathways are incompletely defined. Murine BM conditionally deleted for One-Twenty-Two-1 (Ott1), is able to maintain lifelong hematopoiesis and has preserved numbers of long-term HSCs, yet cannot repopulate nor sustain itself after transplantation against a competitor even when Ott1 is excised after engraftment. We show, specifically under replicative stress, that Ott1-deleted HSCs have a significant reduction of the G(0) cell-cycle fraction associated with self-renewal and undergo early failure. Therefore, Ott1 is required to preserve HSC quiescence during stress but not steady-state hematopoiesis. Reduced tolerance of replicative stress, increased myeloid potential, and greater absolute numbers are mutual characteristics of both Ott1-deleted and aged HSCs, and comparison of their gene expression profiles reveals a shared signature. Ott1-deleted HSCs share multiple aging-associated physiologic changes, including increases in NF-κB activation and DNA damage. Loss of Ott1 causes increased reactive oxygen species; however, antioxidant treatment does not rescue the competitive defect, indicating the existence of additional essential Ott1-dependent HSC pathways. In conclusion, our data establish a requirement for Ott1 in stress hematopoiesis and suggest that Ott1-dependent processes may converge with those affected by aging.

TCR-dependent transformation of mature memory phenotype T cells in mice.

A fundamental goal in cancer research is the identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth, as this has the potential to reveal therapeutic targets. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies. However, the identity of the cells in which mature lymphoid neoplasms are initiated remains unclear. Here, we investigate the origin of peripheral T cell lymphomas using mice in which Snf5, a chromatin remodelling-complex subunit with tumor suppressor activity, could be conditionally inactivated in developing T cells. In this model of mature peripheral T cell lymphomas, the cell of origin was a mature CD44hiCD122loCD8⁺ T cell that resembled a subset of memory cells that has capacity for self-renewal and robust expansion, features shared with stem cells. Further analysis showed that Snf5 loss led to activation of a Myc-driven signaling network and stem cell transcriptional program. Finally, lymphomagenesis and lymphoma proliferation depended upon TCR signaling, establishing what we believe to be a new paradigm for lymphoid malignancy growth. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells are associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers.

Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.

CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8(+) T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8(+) T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.

The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS.

Apc, a negative regulator of the canonical Wnt signaling pathway, is a bona-fide tumor suppressor whose loss of function results in intestinal polyposis. APC is located in a commonly deleted region on human chromosome 5q, associated with myelodysplastic syndrome (MDS), suggesting that haploinsufficiency of APC contributes to the MDS phenotype. Analysis of the hematopoietic system of mice with the Apc(min) allele that results in a premature stop codon and loss of function showed no abnormality in steady state hematopoiesis. Bone marrow derived from Apc(min) mice showed enhanced repopulation potential, indicating a cell intrinsic gain of function in the long-term hematopoietic stem cell (HSC) population. However, Apc(min) bone marrow was unable to repopulate secondary recipients because of loss of the quiescent HSC population. Apc(min) mice developed a MDS/myeloproliferative phenotype. Our data indicate that Wnt activation through haploinsufficiency of Apc causes insidious loss of HSC function that is only evident in serial transplantation strategies. These data provide a cautionary note for HSC-expansion strategies through Wnt pathway activation, provide evidence that cell extrinsic factors can contribute to the development of myeloid disease, and indicate that loss of function of APC may contribute to the phenotype observed in patients with MDS and del(5q).

Do serum biomarkers really measure breast cancer?

BACKGROUND: Because screening mammography for breast cancer is less effective for premenopausal women, we investigated the feasibility of a diagnostic blood test using serum proteins. METHODS: This study used a set of 98 serum proteins and chose diagnostically relevant subsets via various feature-selection techniques. Because of significant noise in the data set, we applied iterated Bayesian model averaging to account for model selection uncertainty and to improve generalization performance. We assessed generalization performance using leave-one-out cross-validation (LOOCV) and receiver operating characteristic (ROC) curve analysis. RESULTS: The classifiers were able to distinguish normal tissue from breast cancer with a classification performance of AUC = 0.82 +/- 0.04 with the proteins MIF, MMP-9, and MPO. The classifiers distinguished normal tissue from benign lesions similarly at AUC = 0.80 +/- 0.05. However, the serum proteins of benign and malignant lesions were indistinguishable (AUC = 0.55 +/- 0.06). The classification tasks of normal vs. cancer and normal vs. benign selected the same top feature: MIF, which suggests that the biomarkers indicated inflammatory response rather than cancer. CONCLUSION: Overall, the selected serum proteins showed moderate ability for detecting lesions. However, they are probably more indicative of secondary effects such as inflammation rather than specific for malignancy.

The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.

Acute megakaryoblastic leukemia (AMKL) is a form of acute myeloid leukemia (AML) associated with a poor prognosis. The genetics and pathophysiology of AMKL are not well understood. We generated a knockin mouse model of the one twenty-two-megakaryocytic acute leukemia (OTT-MAL) fusion oncogene that results from the t(1;22)(p13;q13) translocation specifically associated with a subtype of pediatric AMKL. We report here that OTT-MAL expression deregulated transcriptional activity of the canonical Notch signaling pathway transcription factor recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and caused abnormal fetal megakaryopoiesis. Furthermore, cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL that recapitulated all the features of human AMKL, including megakaryoblast hyperproliferation and maturation block, thrombocytopenia, organomegaly, and extensive fibrosis. Our results establish that concomitant activation of RBPJ (Notch signaling) and MPL (cytokine signaling) transforms cells of the megakaryocytic lineage and suggest that specific targeting of these pathways could be of therapeutic value for human AMKL.

Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen.

The infant leukemia-associated gene Ott1 (Rbm15) has broad regulatory effects within murine hematopoiesis. However, germ line Ott1 deletion results in fetal demise prior to embryonic day 10.5, indicating additional developmental requirements for Ott1. The spen gene family, to which Ott1 belongs, has a transcriptional activation/repression domain and RNA recognition motifs and has a significant role in the development of the head and thorax in Drosophila melanogaster. Early Ott1-deficient embryos show growth retardation and incomplete closure of the notochord. Further analysis demonstrated placental defects in the spongiotrophoblast and syncytiotrophoblast layers, resulting in an arrest of vascular branching morphogenesis. The rescue of the placental defect using a conditional allele with a trophoblast-sparing cre transgene allowed embryos to form a normal placenta and survive gestation. This outcome showed that the process of vascular branching morphogenesis in Ott1-deficient animals was regulated by the trophoblast compartment rather than the fetal vasculature. Mice surviving to term manifested hyposplenia and abnormal cardiac development. Analysis of global gene expression of Ott1-deficient embryonic hearts showed an enrichment of hypoxia-related genes and a significant alteration of several candidate genes critical for cardiac development. Thus, Ott1-dependent pathways, in addition to being implicated in leukemogenesis, may also be important for the pathogenesis of placental insufficiency and cardiac malformations.

H3K79 methylation profiles define murine and human MLL-AF4 leukemias.

We created a mouse model wherein conditional expression of an Mll-AF4 fusion oncogene induces B precursor acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Gene expression profile analysis of the ALL cells demonstrated significant overlap with human MLL-rearranged ALL. ChIP-chip analysis demonstrated histone H3 lysine 79 (H3K79) methylation profiles that correlated with Mll-AF4-associated gene expression profiles in murine ALLs and in human MLL-rearranged leukemias. Human MLL-rearranged ALLs could be distinguished from other ALLs by their H3K79 profiles, and suppression of the H3K79 methyltransferase DOT1L inhibited expression of critical MLL-AF4 target genes. We thus demonstrate that ectopic H3K79 methylation is a distinguishing feature of murine and human MLL-AF4 ALLs and is important for maintenance of MLL-AF4-driven gene expression.

Promoting synergistic research and education in computational biology and drug design.

Supported by US National Science Foundation (NSF) and the International Society of Intelligent Biological Medicine (ISIBM), the IEEE 7th International Conference on Bioinformatics and Bioengineering at Harvard Medical School was designed dynamically in response to the cutting edge synergistic research and education. One of the key components of this academic event is the poster presentation focusing on specific topics to foster collaboration between the computational biology and drug design domains. The Harvard meeting attracted over five hundred scientists, researchers and medical doctors world-wide to present, discuss and exchange their research. The synergies between computational biology and drug design research had been well observed by participants. The poster sessions had been designed to be responsive to the need for synergistic inter/multidisciplinary research and education. A panel of judges was formed to decide the best posters. The papers in this special issue were selected for runners-up of the best poster award by a panel of judges. Authors were then invited to expand their posters into full research papers. Submitted papers were required to contain significant additional scientific detail and were rigorously reviewed by at least three external reviewers. Detailed information regarding the academic event can be found at the White Paper of the IEEE 7th International Conference on Bioinformatics and Bioengineering at Harvard Medical School at BMC Genomics http://www.biomedcentral.com/1471-2164/9/S2/I1.

Breast mass lesions: computer-aided diagnosis models with mammographic and sonographic descriptors.

PURPOSE: To retrospectively develop and evaluate computer-aided diagnosis (CAD) models that include both mammographic and sonographic descriptors. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study. A waiver of informed consent was obtained. Mammographic and sonographic examinations were performed in 737 patients (age range, 17-87 years), which yielded 803 breast mass lesions (296 malignant, 507 benign). Radiologist-interpreted features from mammograms and sonograms were used as input features for linear discriminant analysis (LDA) and artificial neural network (ANN) models to differentiate benign from malignant lesions. An LDA with all the features was compared with an LDA with only stepwise-selected features. Classification performances were quantified by using receiver operating characteristic (ROC) analysis and were evaluated in a train, validate, and retest scheme. On the retest set, both LDAs were compared with radiologist assessment score of malignancy. RESULTS: Both the LDA and ANN achieved high classification performance with cross validation (area under the ROC curve [A(z)] = 0.92 +/- 0.01 [standard deviation] and (0.90)A(z) = 0.54 +/- 0.08 for LDA, A(z) = 0.92 +/- 0.01 and (0.90)A(z) = 0.55 +/- 0.08 for ANN). Results of both models generalized well to the retest set, with no significant performance differences between the validate and retest sets (P > .1). On the retest set, there were no significant performance differences between LDA with all features and LDA with only the stepwise-selected features (P > .3) and between either LDA and radiologist assessment score (P > .2). CONCLUSION: Results showed that combining mammographic and sonographic descriptors in a CAD model can result in high classification and generalization performance. On the retest set, LDA performance matched radiologist classification performance.