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IN THE SPOTLIGHT:

Adventures in Translational Medicine: Gene Expression Profiling and the Electronic Medical Record


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Howard J. Eisen, MD
Drexel University College of Medicine and Hahnemann University Hospital
Philadelphia, Pennsylvania, USA
Howard.Eisen@DrexelMed.edu




I have finally completed all of my patient notes and tasks in our electronic medical record (EMR) to make sure that all of my charges are in before the end of the month, allowing me time to begin my article for ISHLT Links Newsletter. You might be asking: of what relevance is this and how come you are only now writing your article for the Links (Sunday, June 30th), when the deadline was Monday, June 24, 2013? The answer to the second question is: I got an extension. For the answer to the first question, read on.

During my hopefully exhaustive review of my patients' medical records, I came across the results of the gene expression-profiling test that is used to manage patients after cardiac transplantation. I was struck by how a test using changes in the expression of a set of genes in peripheral blood mononuclear cells has in the span of less than a decade been incorporated into the routine laboratory tests that we use to manage our patients. How did this happen and what does the future hold for the assessment of gene expression in the management of transplant patients?

Since the development of the endomyocardial biopsy for the diagnosis of rejection in the 1970s, efforts have been made to find less or noninvasive alternatives. This spawned a cottage industry in noninvasive approaches for the diagnosis of rejection, including echocardiographic, radionuclide scintigraphic and immunologic techniques (1-4). Even former US Senate Majority Leader Bill Frist got into the act with anti-myosin antibodies (5)! (I have no information on whether Congress plans to fund future research efforts in this area). While this research was very interesting and helpful in generating abstracts and publications (what could be called CV polymerase), these techniques and publications did not lead to clinically applicable diagnostic procedures and were forgotten (some of my best publications are among these). Dr. Frist went on to greener pastures in the Senate and the whole field was largely dormant until the development of new molecular techniques, specifically microarray and reverse transcriptase (rt) PCR, allowed the assessment of changes in gene expression in the effector cells of the alloimmune response, mononuclear cells. Several approaches attempted to translate this basic research from bench to bedside. Horwitz identified genes in peripheral blood mononuclear cells whose expression changed at the time of ISHLT Grade 3A (2R) rejection compared to Grade 0 and what happened to expression of these genes after treatment of rejection (6). The CARGO I investigators identified genes whose expression changed with ISHLT Grade 2R rejection compared to Grade 0 (by microarray) and then developed a gene expression profiling (GEP) panel using eleven of those genes (by rt-PCR(7)). This technique was then applied to the general transplant population at participating sites and was used to define "immune activation", above a threshold, from "immune quiescence" below threshold. Ultimately, an FDA approved test was put into clinical practice, representing one of only a very small number of clinical tests utilizing changes in gene expression, and the only one outside of Oncology. Other multi-center and single center studies using this test followed, including CARGO II and the IMAGE trial(8). The latter showed that GEP could be used as an alternative to biopsy for managing patients six months post-transplant and beyond but, as has been pointed out, the event rate was low and the greatest frequency of acute cellular rejection is in the first six months post-transplant. Kobashigawa and colleagues conducted E-IMAGE from months two to six post-transplant and also showed that GEP guided management of cardiac transplant patients had similar outcomes to those undergoing biopsy guided management in a small number of patients. Additional information about the utility of GEP in weaning immunosuppression, the clinical relevance of the change in GEP scores and the identification of "immunoprivileged" patients with low GEP scores who have less rejection and can be managed with less immunosuppression, is also starting to emerge.

Where do we go from here? The present GEP test does not identify patients with antibody mediated rejection or cardiac allograft vasculopathy so other panels of genes will need to be employed to detect these diseases or predict their onset. Biopsy is still required in the first 55 days after transplant (which was not studied in CARGO) for unstable patients and for those with suspected AMR so the endomyocardial biopsy is not going away although its use has decreased. Snyder and colleagues published a study of cell free DNA in whole blood to assess cardiac damage which might be applied when further developed to a variety of cardiac diseases (9). We may see other this and other techniques applied clinically.

You might be wondering after reading these meandering thoughts, what does this have to do with EMR and how could I have used my time more constructively instead of reading this article. EMR also represents translation from basic science (aka the "bench") but in this case from the computing world to the clinical arena. It allows us to document extensively, to see what is happening to our patients across our practice, and to badger those whom we consult and in turn get badgered by those consulting us. It also allows us to prescribe electronically, a component of the euphemistically named "meaningful use". In my case, I finally for the first time in my life, have legible notes (or at least the writing is legible; the content maybe not). I also have a new inexpensive, yet time-consuming hobby, which is completing these notes resulting in higher indirect costs. Personal costs, that is.

Disclosure Statement: The author has no conflicts of interest to disclose. He thanks those who gave him an extension to complete this article but worries that it will only encourage his tendency to procrastinate.


References:

  1. Dengler TJ, Zimmermann R, Braun K, et al. Elevated serum concentrations of cardiac troponin T in acute allograft rejection after human heart transplantation. J Am Coll Cardiol 1998; 32:405.
  2. Bourge R, Eisen H, Hershberger, R, et al. Noninvasive rejection monitoring of cardiac transplants using high resolution intramyocardial electrograms: Initial US multicenter experience. Pacing Clin Electrophysiol 1998; 21:2338.
  3. Moidl R, Chevtchik O, Simon P, et al. Noninvasive monitoring of peak filling rate with acoustic quantification echocardiography accurately detects acute cardiac allograft rejection. J Heart Lung Transplant 1999; 18:194.
  4. Narula J, Acio ER, Narula N, et al. Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat Med 2001; 7:1347.
  5. Frist W, Tsunehiro Y, Segall G et al. Noninvasive detection of human cardiac transplant rejection with indium-111 antimyosin (Fab) imaging. Circulation. 1987;76: Supplement V-81-V-85.
  6. Horwitz PA, Tsai EJ, Putt ME et al. Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression. Circulation. 2004;110:3815-21
  7. Deng, MC, Eisen, HJ, Mehra, MR, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant 2006; 6:150.
  8. Pham MX, Teuteberg JJ, Khoury AG et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010;362:1890-900.
  9. Snyder TM, Khush KK, Valantine HA, Quake SR. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci U S A. 2011;108:6229-34.



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