H A Valantine

Stanford Medicine, Stanford, California, United States

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Publications (194)1071.35 Total impact

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    ABSTRACT: Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.
    Science translational medicine 06/2014; 6(241):241ra77. · 10.76 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S175. · 5.11 Impact Factor
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    ABSTRACT: Gene expression profiling test scores have primarily been used to identify heart transplant recipients who have a low probability of rejection at the time of surveillance testing. We hypothesized that the variability of gene expression profiling test scores within a patient may predict risk of future events of allograft dysfunction or death. Patients from the IMAGE study with rejection surveillance gene expression profiling tests performed at 1- to 6-month intervals were selected for this cohort study. Gene expression profiling score variability was defined as the standard deviation of an individual's cumulative test scores. Gene expression profiling ordinal score (range, 0-39), threshold score (binary value=1 if ordinal score ≥34), and score variability were studied in multivariate Cox regression models to predict future clinical events. Race, age at time of transplantation, and time posttransplantation were significantly associated with future events in the univariate analysis. In the multivariate analyses, gene expression profiling score variability, but not ordinal scores or scores over threshold, was independently associated with future clinical events. The regression coefficient P values were <0.001, 0.46, and 0.773, for gene expression profiling variability, ordinal, and threshold scores, respectively. The hazard ratio for a 1 unit increase in variability was 1.76 (95% CI, 1.4-2.3). The variability of a heart recipient's gene expression profiling test scores over time may provide prognostic utility. This information is independent of the probability of acute cellular rejection at the time of testing that is rendered from a single ordinal gene-expression profiling test score.
    Transplantation 03/2014; 97(6):708-14. · 3.78 Impact Factor
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    ABSTRACT: Gene expression profiling test scores have primarily been used to identify heart transplant recipients who have a low probability of rejection at the time of surveillance testing. We hypothesized that the variability of gene expression profiling test scores within a patient may predict risk of future events of allograft dysfunction or death. Patients from the IMAGE study with rejection surveillance gene expression profiling tests performed at 1- to 6-month intervals were selected for this cohort study. Gene expression profiling score variability was defined as the standard deviation of an individual's cumulative test scores. Gene expression profiling ordinal score (range, 0-39), threshold score (binary value=1 if ordinal score ≥34), and score variability were studied in multivariate Cox regression models to predict future clinical events. Race, age at time of transplantation, and time posttransplantation were significantly associated with future events in the univariate analysis. In the multivariate analyses, gene expression profiling score variability, but not ordinal scores or scores over threshold, was independently associated with future clinical events. The regression coefficient P values were <0.001, 0.46, and 0.773, for gene expression profiling variability, ordinal, and threshold scores, respectively. The hazard ratio for a 1 unit increase in variability was 1.76 (95% CI, 1.4-2.3). The variability of a heart recipient's gene expression profiling test scores over time may provide prognostic utility. This information is independent of the probability of acute cellular rejection at the time of testing that is rendered from a single ordinal gene-expression profiling test score.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    Transplantation 01/2014; · 3.78 Impact Factor
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    ABSTRACT: There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence.
    Cell 11/2013; 155(5):1178-1187. · 31.96 Impact Factor
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    ABSTRACT: To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score>37% = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.
    PLoS ONE 01/2013; 8(12):e82153. · 3.53 Impact Factor
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    ABSTRACT: The influence of donor-transmitted coronary atherosclerosis (DA) on plaque progression during the first year after cardiac transplantation (Tx) is unknown. Serial 3-dimensional intravascular ultrasound (IVUS) studies were performed within 8 weeks (baseline; BL) and at 1 year after Tx in 38 recipients. On the basis of maximum intimal thickness (MIT) at BL, recipients were divided into DA group (DA+; MIT≥0.5 mm, n=23) or non-DA group (DA-; MIT<0.5 mm, n=15). Plaque, lumen, and vessel volume indexes were calculated by volume/measured length (mm/mm) in the left anterior descending artery. Univariate and multivariate regression analyses were attempted to reveal clinical predictors of change in coronary dimensions. During the first year after Tx, plaque volume index increased significantly in DA+ group, but did not change in DA- Group (DA+, 3.0±1.5 to 4.1±1.5 mm/mm, P<0.0001: DA-, 1.2±0.4 to 1.3±0.5 mm/mm, P=0.53). In both groups vessel volume index decreased significantly (DA+, 16.3±3.6 to 14.6±3.3 mm/mm, P=0.003: DA-, 13.5±4.1 to 12.0±3.3 mm/mm, P=0.01), as did lumen volume index (DA+, 13.2±3.1 to 10.5±2.7 mm/mm, P<0.0001: DA-, 12.2±3.7 to 10.7±3.0 mm/mm, P=0.004). Univariate and multivariate regression analyses revealed that DA was one of the strongest predictors for plaque progression. DA was associated with significant plaque progression during the first year after Tx, and in conjunction with negative remodeling, may be an important determinant of cardiac allograft vasculopathy.
    Transplantation 06/2011; 91(12):1406-11. · 3.78 Impact Factor
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    ABSTRACT: Recent studies suggest that students' feelings of fit with a residency program substantially influence students' ranking of the program. As diversity issues become increasingly focal concerns, we investigate how perception of gender and racial diversity of a program influences students' rankings of the program. We focus on students pursuing surgical specialties and ask whether diversity concerns are more prominent among applicants to surgical programs than among applicants to nonsurgical programs. We invited all interviewees at all residency programs at the Stanford University School of Medicine to participate in our study in the spring of 2009. Nineteen residency programs, amounting to 1,657 residency interviewees, participated. Sixty-eight percent (n = 1,132) responded to the survey. Women and under-represented minority applicants differ in their assessments from male and non-under-represented minority applicants because women applying to surgical programs and under-represented minority students are less likely than others to perceive their prospective programs as diverse. However, perceived program diversity is an important factor that positively influences the program ranking decision for women and minorities pursuing surgical training. Surgical training programs that promote gender and racial diversity will likely be more successful in attracting women and minority students because women and minorities are especially sensitive to program diversity in both their perceptions and rankings of programs. Promoting women and minorities within programs and connecting women and minority applicants to outreach programs and mentors is pertinent to the recruitment of these traditionally under-represented groups to surgical programs.
    Journal of the American College of Surgeons 06/2011; 213(2):294-305. · 4.50 Impact Factor
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    ABSTRACT: Treatment of acute rejection (AR) in heart transplantation relies on histopathological grading of endomyocardial biopsies according to International Society for Heart and Lung Transplantation guidelines. Intragraft gene expression profiling may be a way to complement histological evaluation. Transcriptional profiling was performed on 26 endomyocardial biopsies, and expression patterns were compared with the 1990 International Society for Heart and Lung Transplantation AR grades. Importantly, transcriptional profiles from settings with an equivalent AR grade appeared the same. In addition, grade 0 profiles could not be distinguished from 1A profiles, and grade 3A profiles could not be distinguished from 3B profiles. Comparing the AR groupings (0+1A, 1B, and 3A+3B), 0+1A showed more striking differences from 1B than from 3A+3B. When these findings were extrapolated to the 2005 revised guidelines, the combination of 1A and 1B into a single category (1R) appears to have brought together endomyocardial biopsies with different underlying processes that are not evident from histological evaluation. Grade 1B was associated with upregulated immune response genes, as 1 categorical distinction from grade 1A. Although grade 1B was distinct from the clinically relevant AR grades 3A and 3B, all of these grades shared a small number of overlapping pathways consistent with common physiological underpinnings. The gene expression similarities and differences identified here in different AR settings have the potential to revise the clinical perspective on acute graft rejection, pending the results of larger studies.
    Circulation 05/2011; 123(20):2236-43. · 15.20 Impact Factor
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    ABSTRACT: Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.
    Clinical Transplantation 05/2011; 25(5):E475-86. · 1.63 Impact Factor
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    ABSTRACT: Purpose AlloMap® is a non-invasive gene expression profile (GEP) test with a high negative predictive value for moderate/severe cellular rejection. We have observed a cohort of patients with consistently low GEP scores. Whether this reflects a group of patients with unique characteristics and a more quiescent immunological state manifest by improved outcomes is of interest in this study. Methods and Materials A low GEP score was defined within the lowest quartile of all GEP scores from a large database of all patients with at least 3 tests performed at the reference lab. Two groups from the IMAGE multicenter clinical outcomes study were retrospectively defined: Group 1 had a mean score in the lowest quartile (GEP ≤27.5), and patients with scores greater than 2 standard deviations from the mean were excluded; Group 2 had mean scores <34, the clinically accepted threshold for low rejection risk, that did not meet Group 1 criteria. Clinical outcomes of interest included a composite primary endpoint (rejection with hemodynamic compromise, graft dysfunction due to other causes, and death/retransplantation), any treated rejection, left ventricular ejection fraction (LVEF), and hospitalizations. Results We evaluated 1684 scores from 353 patients from IMAGE. Group 1 had 59 patients with 250 scores; Group 2 had 294 patients with 1434 scores. Basic demographics including age, gender, and race were similar between groups. Mean time since transplant was 21 months in both groups. Outcomes are shown below. Table 1. View Within Article Conclusions Patients with consistently low GEP scores have a significantly lower incidence of adverse outcomes compared to patients in Group 2 despite similar demographics. With further characterization of this group, and if validated on a larger scale, more personalized post-transplant care to tailor immunosuppression down may be possible.
    The Journal of Heart and Lung Transplantation 04/2011; 30(4). · 5.11 Impact Factor
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    ABSTRACT: It is challenging to monitor the health of transplanted organs, particularly with respect to rejection by the host immune system. Because transplanted organs have genomes that are distinct from the recipient's genome, we used high throughput shotgun sequencing to develop a universal noninvasive approach to monitoring organ health. We analyzed cell-free DNA circulating in the blood of heart transplant recipients and observed significantly increased levels of cell-free DNA from the donor genome at times when an endomyocardial biopsy independently established the presence of acute cellular rejection in these heart transplant recipients. Our results demonstrate that cell-free DNA can be used to detect an organ-specific signature that correlates with rejection, and this measurement can be made on any combination of donor and recipient. This noninvasive test holds promise for replacing the endomyocardial biopsy in heart transplant recipients and may be applicable to other solid organ transplants.
    Proceedings of the National Academy of Sciences 03/2011; 108(15):6229-34. · 9.81 Impact Factor
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    ABSTRACT: Academic couples constitute 36% of the US professoriate. Universities are in the midst of a major transition in hiring practices to support these and other faculty with working partners. However, less is known about academic couples among medical school faculty and surgical specialties specifically. This study was designed to address this gap. In 2006-2007, the Michelle R Clayman Institute for Gender Research at Stanford University designed and administered the "Managing Academic Careers Survey" to nearly 30,000 full-time faculty across all academic fields at leading research universities nationwide. This study included 2,475 medical school faculty survey respondents at 12 participating institutions. Main outcomes measures were academic partner status; number of journal articles/chapters during career; and applications to other academic position(s) in last 5 years. A total of 73.3% of medical school faculty respondents were in dual-career partnerships (where both partners actively pursue employment) and 32.2% had an academic partner. Sixty-nine percent of academic partners were also in medical schools. Women faculty were more likely than men to have an academic partner. Among surgery faculty, 40% of women had an academic partner, as compared with 29.3% of men. In fully adjusted regression models, faculty with academic partners had higher publication counts than other faculty, and had higher odds of applying to other academic positions. Academic couples constitute one-third of all medical school faculty. They represent a productive and potentially mobile component of the medical faculty workforce. Because women had a higher rate of academic partnering, dual-career academic hiring policies are especially important for recruitment and retention of female faculty in surgical specialties.
    Journal of the American College of Surgeons 02/2011; 212(3):310-9. · 4.50 Impact Factor
  • K. K. Khush, J. Kubo, M. Desai, H. A. Valantine
    Journal of Heart and Lung Transplantation - J HEART LUNG TRANSPLANT. 01/2011; 30(4).
  • K. K. Khush, T. M. Snyder, S. R. Quake, H. A. Valantine
    Journal of Heart and Lung Transplantation - J HEART LUNG TRANSPLANT. 01/2011; 30(4).
  • Journal of Heart and Lung Transplantation - J HEART LUNG TRANSPLANT. 01/2011; 30(4).
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    ABSTRACT: Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)
    New England Journal of Medicine 04/2010; 362(20):1890-900. · 54.42 Impact Factor
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    ABSTRACT: Serum proteins are routinely used to diagnose diseases, but are hard to find due to low sensitivity in screening the serum proteome. Public repositories of microarray data, such as the Gene Expression Omnibus (GEO), contain RNA expression profiles for more than 16,000 biological conditions, covering more than 30% of United States mortality. We hypothesized that genes coding for serum- and urine-detectable proteins, and showing differential expression of RNA in disease-damaged tissues would make ideal diagnostic protein biomarkers for those diseases. We showed that predicted protein biomarkers are significantly enriched for known diagnostic protein biomarkers in 22 diseases, with enrichment significantly higher in diseases for which at least three datasets are available. We then used this strategy to search for new biomarkers indicating acute rejection (AR) across different types of transplanted solid organs. We integrated three biopsy-based microarray studies of AR from pediatric renal, adult renal and adult cardiac transplantation and identified 45 genes upregulated in all three. From this set, we chose 10 proteins for serum ELISA assays in 39 renal transplant patients, and discovered three that were significantly higher in AR. Interestingly, all three proteins were also significantly higher during AR in the 63 cardiac transplant recipients studied. Our best marker, serum PECAM1, identified renal AR with 89% sensitivity and 75% specificity, and also showed increased expression in AR by immunohistochemistry in renal, hepatic and cardiac transplant biopsies. Our results demonstrate that integrating gene expression microarray measurements from disease samples and even publicly-available data sets can be a powerful, fast, and cost-effective strategy for the discovery of new diagnostic serum protein biomarkers.
    PLoS Computational Biology 01/2010; 6(9). · 4.87 Impact Factor
  • The Journal of Heart and Lung Transplantation. 01/2010; 29(2):S38–S39.
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    ABSTRACT: During the past 25 years, advances in immunosuppression and the use of selective anti-microbial prophylaxis have progressively reduced the risk of infection after heart transplantation. This study presents a historical perspective of the changing trends of infectious disease after heart transplantation. Infectious complications in 4 representative eras of immunosuppression and anti-microbial prophylaxis were analyzed: (1) 38 in the pre-cyclosporine era (1978-1980), (2) 72 in the early cyclosporine era (1982-1984), where maintenance immunosuppression included high-dose cyclosporine and corticosteroid therapy; (3) 395 in the cyclosporine era (1988-1997), where maintenance immunosuppression included cyclosporine, azathioprine, and lower corticosteroid doses; and (4) 167 in the more recent era (2002-2005), where maintenance immunosuppression included cyclosporine and mycophenolate mofetil. The overall incidence of infections decreased in the 4 cohorts from 3.35 episodes/patient to 2.03, 1.35, and 0.60 in the more recent cohorts (p < 0.001). Gram-positive bacteria are emerging as the predominant cause of bacterial infections (28.6%, 31.4%, 51.0%, 67.6%, p = 0.001). Cytomegalovirus infections have significantly decreased in incidence and occur later after transplantation (88 +/- 77 days, pre-cyclosporine era; 304 +/- 238 days, recent cohort; p < 0.001). Fungal infections also decreased, from an incidence of 0.29/patient in the pre-cyclosporine era to 0.08 in the most recent era. A major decrease in Pneumocystis jiroveci and Nocardia infections has also occurred. The overall incidence and mortality associated with infections continues to decrease in heart transplantation and coincides with advances in immunosuppression, the use of selective anti-microbial prophylaxis, and more effective treatment regimens.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 10/2009; 29(3):306-15. · 3.54 Impact Factor

Publication Stats

4k Citations
1,071.35 Total Impact Points

Institutions

  • 1987–2014
    • Stanford Medicine
      • • Division of Cardiovascular Medicine
      • • Falk Cardiovascular Research Center
      • • Department of Surgery
      • • Department of Medicine
      Stanford, California, United States
  • 1990–2009
    • Stanford University
      • • Division of Cardiovascular Medicine
      • • Department of Cardiothoracic Surgery
      • • Falk Cardiovascular Research Center
      Stanford, CA, United States
  • 2008
    • Policlinico S.Orsola-Malpighi
      Bolonia, Emilia-Romagna, Italy
    • Medical University of Vienna
      Wien, Vienna, Austria
  • 2007
    • University of Bologna
      • Institute of Cardiology
      Bologna, Emilia-Romagna, Italy
  • 2006
    • Deutsches Herzzentrum Berlin
      Berlín, Berlin, Germany
  • 2001
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 1998
    • University of California, Los Angeles
      Los Angeles, California, United States