Findings of Scientific Misconduct

AGENCY:

Office of the Secretary, HHS.

ACTION:

Notice.

SUMMARY:

Notice is hereby given that the Office of Research Integrity (ORI) and the Assistant Secretary for Health have taken final action in the following case:

Zhenhai Yao, M.D., Ph.D., The University of North Carolina at Chapel Hill: On August 20, 2002, the U.S. Public Health Service (PHS) entered into a Voluntary Exclusion Agreement with The University of North Carolina at Chapel Hill (UNC) and Zhenhai Yao, M.D., Ph.D., an Associate Professor of Anesthesiology, School of Medicine at UNC. Based on the UNC Report, the respondent's admissions, and additional analysis conducted by ORI in its oversight review, PHS found that Dr. Yao engaged in scientific misconduct in research funded by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH).

Specifically, PHS and UNC found that Dr. Yao:

(1) Falsified two flourescent micrographs for figures presented in three NIH grant applications:

A. Figure 5, p. 28, in a funded grant application in 1 R01 HL067416-01, “Mechanism of Preconditioning and Cardiac Apoptosis,” submitted to NIH on May 31, 2000;

B. Figure 6, p. 33, in a funded grant application in 1 R01 HL68250-01, “Free Radicals, PKCδ Signal Acetylcholine Preconditioning,” submitted to NIH on September 9, 2000; and

C. Figure 7, p. 25, in an unfunded grant application in 1 R01 HL66230-01A1, “Nitric Oxide and Opioid Preconditioning,” Submitted to NIH on July 2, 2001.

Dr. Yao falsely claimed that two fluorescent micrographs in the figure represented neonatal rat cells transfected with an adenovirus-derived vector, when the cells actually were chick cells transfected with a cytomegalovirus-based vector, which he had taken from another scientist at the University of Chicago.

(2) Falsified the same two fluorescence micrographs of CMV-transfected chick cells described in Issue 1, above, by misrepresenting their description as embryonic chick cells transfected with pcDNA, with and without green fluorescent protein, for Figure 13 on p. 30 in an unfunded NIH grant application, 1 R01 HL66230-01, “Molecular Mechanisms of Opioids in Myocardial Ischemia,” submitted January 21, 2000.

(3) Falsified a flow cytometry histogram in Figure 1B on p. 22 of NIH application R01 HL66230-01A1, by claiming the histogram represented results with rat myocardiocyte cultures treated with an opiate antagonist (staurosporine).

However, this histogram had been published by Liu, H., McPherson, B.C., & Yao, Z. “Preconditioning Attentuates Apoptosis and Necrosis: Role of Protein Kinase Cε and -δ Isoforms.” Am. J. Physiology Heart Circ Physiol. 281:H404-H410, 2001, as Figure 1f showing the result from embryonic chick cells treated for 12 hours with deoxy-glucose in the absence of oxygen (simulated ischemia).

(4) Falsified claims about research results in NIH grant application R01 HL66230-01A1, by claiming that data in Figure 3 on p. 23 represented experiments on cultures of neonatal rat cardiomyocytes as an in vitro model of hypoxia-reoxygenation, shown as data from four separate experiments measuring apoptosis by different means.

The data in the four separate experiments portrayed in Figure 3 are identical to Figure 1, p. 2009, in the publication by Liu, H., Zhang, H.Y., McPherson, B.C., Baman, T., Roth, S., Shao, Z., Zhu, X., & Yao, Z. “Role of Opioid δ₁ Receptors, Mitochondrial K_ATP Channels, and Protein Kinase C during Cardiocyte Apoptosis. J. Mol. Cell. Cardio. 33:2001-2014, 2001, which were reported as the results from experiments on cultures of embryonic chick cardiocytes.

(5) Falsified the micrographs in panels a and d, Figure 1, p. 2009, in the publication by Liu, H. et al., J. Mol. Cell. Cardiol. 33:2001-2014, 2001, by claiming they represented TUNEL data showing normal media and opioid antagonist (BTNX)-treated cultures of chick cardiocytes, respectively.

The same micrographs had been reported by Liu, H. et al., Am. J. Physiology Heart Circ Physiol. 281:H404-H410, 2001, in Figure 1 (panels a and e) and in Figure 2 (panels a and b), as representing cardiocyte cultures exposed for 24 hours to deoxy-glucose and no oxygen (simulated ischemia).

(6) Falsified the physiological effects of gene transduction into hearts, by copying and re-using the same pressure tracing for untreated rats as he did for rats purportedly treated by intracardial injection with adenovirus (AdEGFP) in:

A. Figure 11, p. 26, in unfunded NIH grant application R01 HL66230-01A1;

B. Figure 9, p. 30, in funded NIH grant application R01 HL67416-01;

C. Figure 9, p. 34, in funded NIH grant application R01 HL68250-01; and

D. Figure 8, p. 30, in funded NIH grant application 1 K08 HL03881-01.

(7) Falsified data in panels c and d in Figure 13, p. 26, in NIH grant application R01 HL66230-01A1. Dr. Yao claimed that panel c represented a TUNEL assay on histological sections of myocardium from a rat transfected with Ad.βgal and subjected to ischemia-reperfusion and that panel d represented a tissue section from a rat transfected with Ad.PKCδ-FL.

Panel c is a horizontally compressed copy of panel b, purported to be a non-transfected rat subjected to ischemia-reperfusion, and panel d is a horizontally expanded version of panel a, purported to be a sham-operated, non-transfected control.

(8) Falsified the claims about the micrograph of ischemic data (“panel b” in issue 7, above) reported as:

A. Figure 11, p. 31, in R01 HL67416-01 (submitted May 31, 2000); and

B. Figure 12, p. 35, in R01 HL68250-01 (submitted September 29, 2000).

In both examples, the figures, which are identical, consist of two panels purported to be TUNEL data showing sham operated controls (panel a) and the effect of transient ischemia for 30 minutes (panel b). However, these data are identical to Figure 10, p. 32, in NIH application K08 HL03881-01, reported a control and the effect of nontransient ischemia, i.e., 20 hours of ischemia followed by 24 hours of reperfusion.

(9) Falsified data in Figure 14 on p. 27 in NIH grant application R01 HL66230-01A1, as representing a gel electrophoresis data from an in vivo experiment on rat myocardial ischemia.

However, the same data was represented as Figure 3, p. 23, of the application (and also as in Figure 1, J. Cell. Mol. Cardiol. 33:2007-2014, 2001), as results from a study of embryonic chick heart cell cultures for the effect of preconditioning on opioid receptors. Furthermore, Dr. Yao falsified the stated size of the fragments in the DNA marker ladder by altering the position of the molecular weight markers in Figure 14.

(10) Falsified Figure 3, p. 27, in 1 R01 HL67416-01, a DNA-laddering gel electrophoresis experiment, showing that apoptosis in cardiocyte cultures is significantly increased by staurosporin and by 12 hours of simulated ischemia.

The same data was shown in Figure 1, p. 26, in application HL03881-07 showing that apoptosis is significantly increased by 10 μM NE and by 15 nM TNF-α.

The research misconduct was significant because Dr. Yao's research involved the fundamental mechanisms for cardiac cell injury and pathogenesis after a heart attack. The falsified data were significant to reviewers' opinions on funding because they were advanced as preliminary results showing successful new experiments extending his experimental model to adult rat hearts.

Dr. Yao has entered into a Voluntary Exclusion Agreement in which he has voluntarily agreed:

(1) To exclude himself from any contracting or subcontracting with any agency of the United States Government and from eligibility for, or involvement in, nonprocurement transactions (e.g., grants and cooperative agreements) of the United States Government as defined in 45 CFR part 76 (Debarment Regulations) for a period of five (5) years, beginning on August 20, 2002;

(2) to exclude himself from serving in any advisory capacity to PHS, including but not limited to service on any PHS advisory committee, board, and/or peer review committee, or as a consultant for a period of five (5) years, beginning on August 20, 2002; and

(3) to submit a letter to the Journal of Molecular and Cellular Cardiology requesting retraction of Figure 1 in the article by Hui Liu, et al., J. Mol. Cell. Cardiol. 33:2001-2014, 2001, within 30 days of notification of this action. This requirement will be noted on the ALERT System until Dr. Yao sends a copy of the retraction letter to ORI.

FOR FURTHER INFORMATION CONTACT:

Director, Division of Investigative Oversight, Office of Research Integrity, 5515 Security Lane, Suite 700, Rockville, MD 20852, (301) 443-5330.