Over the last >20 years, we have co‐developed the rationale for the first diagnostic and prognostic leukocyte gene expression profiling (GEP) biomarker test in transplantation medicine that gained ...US‐FDA‐regulatory clearance and international evidence‐based medicine guideline acceptance to rule out moderate/severe acute cellular cardiac allograft rejection without invasive endomyocardial biopsies (EMB). Based on this test, a non‐invasive clinical algorithm was implemented since 2005. After clinical implementation, this GEP‐based monitoring in direct comparison with an EMB‐based strategy was non‐inferior with respect to detection of clinical rejection, defined as new onset allograft dysfunction with/without histology of ACR, re‐transplantation or death, and at the same time improved patient satisfaction. Subsequently, we demonstrated the test's capacity when used as serial monitoring tool to predict these clinical rejection events. In this Personal Viewpoint article, I will discuss the various decision‐making branching points that were made in the AlloMap biomarker test development to inform future genomic biomarker test development projects.
The Cancer Genome Atlas (TCGA) is a pool of molecular data sets publicly accessible and freely available to cancer researchers anywhere around the world. However, wide spread use is limited since an ...advanced knowledge of statistics and statistical software is required.
In order to improve accessibility we created Web-TCGA, a web based, freely accessible online tool, which can also be run in a private instance, for integrated analysis of molecular cancer data sets provided by TCGA. In contrast to already available tools, Web-TCGA utilizes different methods for analysis and visualization of TCGA data, allowing users to generate global molecular profiles across different cancer entities simultaneously. In addition to global molecular profiles, Web-TCGA offers highly detailed gene and tumor entity centric analysis by providing interactive tables and views.
As a supplement to other already available tools, such as cBioPortal (Sci Signal 6:pl1, 2013, Cancer Discov 2:401-4, 2012), Web-TCGA is offering an analysis service, which does not require any installation or configuration, for molecular data sets available at the TCGA. Individual processing requests (queries) are generated by the user for mutation, methylation, expression and copy number variation (CNV) analyses. The user can focus analyses on results from single genes and cancer entities or perform a global analysis (multiple cancer entities and genes simultaneously).
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background The Organ Care System is the only clinical platform for ex-vivo perfusion of human donor hearts. The system preserves the donor heart in a warm beating state during transport from ...the donor hospital to the recipient hospital. We aimed to assess the clinical outcomes of the Organ Care System compared with standard cold storage of human donor hearts for transplantation. Methods We did this prospective, open-label, multicentre, randomised non-inferiority trial at ten heart-transplant centres in the USA and Europe. Eligible heart-transplant candidates (aged >18 years) were randomly assigned (1:1) to receive donor hearts preserved with either the Organ Care System or standard cold storage. Participants, investigators, and medical staff were not masked to group assignment. The primary endpoint was 30 day patient and graft survival, with a 10% non-inferiority margin. We did analyses in the intention-to-treat, as-treated, and per-protocol populations. This trial is registered with ClinicalTrials.gov , number NCT00855712. Findings Between June 29, 2010, and Sept 16, 2013, we randomly assigned 130 patients to the Organ Care System group (n=67) or the standard cold storage group (n=63). 30 day patient and graft survival rates were 94% (n=63) in the Organ Care System group and 97% (n=61) in the standard cold storage group (difference 2·8%, one-sided 95% upper confidence bound 8·8; p=0·45). Eight (13%) patients in the Organ Care System group and nine (14%) patients in the standard cold storage group had cardiac-related serious adverse events. Interpretation Heart transplantation using donor hearts adequately preserved with the Organ Care System or with standard cold storage yield similar short-term clinical outcomes. The metabolic assessment capability of the Organ Care System needs further study. Funding TransMedics.
A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene ...Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance.
Blood samples for GEP testing (AlloMap(®), CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0-39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2-6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively.
For ≥2-6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection.
In parallel to the clinical maturation of heart transplantation over the last 50 years, rejection testing has been revolutionized within the systems biology paradigm triggered by the Human Genome ...Project.
We have co-developed the first FDA-cleared diagnostic and prognostic leukocyte gene expression profiling biomarker test in transplantation medicine that gained international evidence-based medicine guideline acceptance to rule out moderate/severe acute cellular cardiac allograft rejection without invasive endomyocardial biopsies. This work prompted molecular re-classification of intragraft biology, culminating in the identification of a pattern of intragraft myocyte injury, in addition to acute cellular rejection and antibody-mediated rejection. This insight stimulated research into noninvasive detection of myocardial allograft injury. The addition of a donor-organ specific myocardial injury marker based on donor-derived cell-free DNA further strengthens the noninvasive monitoring concept, combining two complementary noninvasive blood-based measures, host immune activity-related risk of acute rejection as well as cardiac allograft injury.
This novel complementary noninvasive heart transplant monitoring strategy based on leukocyte gene expression profiling and donor-derived cell-free DNA that incorporates longitudinal variability measures provides an exciting novel algorithm of heart transplant allograft monitoring. This algorithm's clinical utility will need to be tested in an appropriately designed randomized clinical trial.
Abstract
With its Firebrowse service (http://firebrowse.org/) the Broad Institute is making large-scale multi-platform omics data analysis results publicly available through a Representational State ...Transfer (REST) Application Programmable Interface (API). Querying this database through an API client from an arbitrary programming environment is an essential task, allowing other developers and researchers to focus on their analysis and avoid data wrangling. Hence, as a first result, we developed a workflow to automatically generate, test and deploy such clients for rapid response to API changes. Its underlying infrastructure, a combination of free and publicly available web services, facilitates the development of API clients. It decouples changes in server software from the client software by reacting to changes in the RESTful service and removing direct dependencies on a specific implementation of an API. As a second result, FirebrowseR, an R client to the Broad Institute’s RESTful Firehose Pipeline, is provided as a working example, which is built by the means of the presented workflow. The package’s features are demonstrated by an example analysis of cancer gene expression data.
Database URL:
https://github.com/mariodeng/
There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs).
We evaluated agreement within the CARGO II ...pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers).
Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both.
The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria--EMB based or otherwise--that correspond better with the pathophysiology of the transplanted heart.
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