Solid Gold, or Liquid Gold?

he endomyocardial biopsy has been the gold standard for diagnosis of heart transplant rejection since first pioneered by surgeon Dr Phillip Caves and pathologist Dr Margaret Billingham at Stanford in the early 1970s.A decade earlier, in Japan, a percutaneous method of obtaining cardiac tissue had been reported 1 but never used in heart transplant recipients.Dr Caves obtained a bioptome from Japan and improved the design using a canine model of heart transplantation. 2 Dr Billingham prepared the endomyocardial biopsy (EMB) samples and cataloged the pathological findings, and the field of heart transplant pathology was born. 3 Since then, sensitive noninvasive diagnostic tools for early detection of transplant injury have remained an unmet need in heart transplantation.Many noninvasive methods have been evaluated, including parameters from electrocardiography, echocardiography, cardiac magnetic resonance imaging, and positron emission tomography, as well as biomarkers such as troponin and B-type natriuretic peptide; however, all these methods offer limited sensitivity and specificity.Noninvasive peripheral gene expression testing is the most promising noninvasive alternative to the EMB, with a 99% negative predictive value for acute cellular rejection (ACR; AlloMap, CareDx, Inc). 4 However, peripheral gene expression testing offers limited positive predictive value for ACR and was not designed to detect antibody-mediated rejection (AMR), a major barrier as the treatment, surveillance, and prognosis of AMR differ greatly from ACR. 5 Donor-derived cell-free DNA (ddcfDNA) is a new noninvasive approach to detect rejection that may improve on peripheral gene expression testing.The discovery of cell-free DNA dates back to 1948, when it was identified in the sera of patients with cancer.6 The significance of this observation went unrecognized for decades, although with advances in genetic sequencing cell-free DNA is now a biomarker for prenatal testing and cancer.In organ transplantation, ddcfDNA was proposed as a noninvasive indicator of graft injury on the basis of the hypothesis that acute rejection causes cell death in the allograft, which leads to increased levels of ddcfDNA in the blood of transplant recipients.7 However, early technologies to quantify ddcfDNA in transplant patients were costly and often impractical, requiring either sex mismatch between donor and recipient (to use the Y chromosome to distinguish donor from recipient DNA) 8 or previous genotyping of the donor and recipient.9 These barriers were overcome with the development of a targeted amplification, next-generation sequencing assay relying on single nucleotide polymorphisms.10 For the ddcfDNA assay to be applicable to different transplant recipients without requiring separate genotyping of either donor or recipient, specific single Solid Gold, or Liquid Gold?