Findings of Research Misconduct

Hat trick from ORI … (the first serving as a reminder why ORI is outside of the NIH)

Notice is hereby given that ORI has taken final action in the following case:

Based on the report of an investigation conducted by the NIH and additional analysis by ORI in its oversight review, ORI found that Bijan Ahvazi, PhD, former Director of the Laboratory of X-ray Crystallography, NIAMS, engaged in research misconduct in research supported by the Intramural Program.

ORI found that Respondent engaged in research misconduct by falsifying data related to or in the following published papers:

  1. Ahvazi, B., Boeshans, K.M., Idler, W., Baxa, U., & Steinert, P.M. “Structural basis for the coordinated regulation of transglutaminase 3 by guanine nucleotides and calcium/magnesium.” J. Biol. Chem. 279(8):7180-92, 2004 Feb 20 (withdrawn) (hereinafter “JBC 2004a”)
  2. Ahvazi, B., Boeshans, K.M., & Steinert, P.M. “Crystal structure of transglutaminase 3 in complex with BMP: Structural basis for nucleotide specificity.” J. Biol. Chem. 279:26716-25, 2004 (withdrawn) (hereinafter “JBC 2004b”)
  3. Ahvazi, B., Boeshans, K.M., Idler, W.,& Cooper, A.J.L. “Crystal structure of transglutaminase 3-cystamine complex: Binding of two cystamines to the nucleotide-binding pocket.” M6:06060, Submitted to J. Biol. Chem., 2006 (rejected) (hereinafter “JBC 2006”).

Specifically, ORI finds that Respondent:

1. falsely labeled Figure 3A in JBC 2004b representing an isothermal calorimetric titration experiment using guanine monophosphate (GMP) and transglutaminase 3 (TGase 3) when the figure was actually a relabeled version of an unrelated experiment that Respondent previously published as Figure 1A in JBC 2004a.

2. falsified Figure 4B, Figure 4C, and Figure 6D in JBC 2004b and Figure 5E in JBC 2006, by altering the original data in the following ways to represent the desired experiment:

a. falsified Figure 4B in JBC 2004b, by adding multiple data points to titration curves for four different concentrations of TGase 3 bound by different concentrations of tagged GTP[gamma]S and deleting 2 outlying data points from one of the curves

b. falsified Figure 4C in JBC 2004 b, representing a competition assay for the release of tagged GTPγS bound to TGase 3, by (1) falsely claiming that the release of the tagged nucleotide occurred with the addition of untagged GMP, when the result was from an assay using untagged GDP, (2) adding additional data points onto the titration curves, and (3) altering the scale of the abscissa

c. falsified Figure 6D in JBC 2004b, by using the false Figure 4B to also represent an additional competition experiment using unmodified nucleotide analog compounds and ATP; specifically, Respondent (1) falsified the units and labels of the axes, (2) falsified the labels of the curves, and (3) vertically inverted the curves

d. falsified Figure 5E in the JBC 2006 manuscript, representing a competition experiment for the release of tagged GTPγS bound to TGase 3 with the addition of cystamine, when the actual experiment was a competition experiment with the addition of untagged nucleotides.

Dr. Ahvazi has entered into a Voluntary Settlement Agreement and has voluntarily agreed for a period of 2 years, beginning on October 7, 2014:

(1) To have his U.S. PHS research supervised and to notify any employer(s)/institution(s) at which he may participate in PHS funded projects of the terms of his supervision; Respondent agrees that prior to the submission of an application for PHS support for a research project on which the Respondent’s participation is proposed and prior to Respondent’s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondent’s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondent’s research; Respondent agrees that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agrees to maintain responsibility for compliance with the agreed upon supervision plan;

(2) that any institution employing him to work on PHS-supported projects shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and

(3) to exclude himself voluntarily 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.


Notice is hereby given that ORI has taken final action in the following case:

Based on the report of an investigation conducted by UT Southwestern and analysis conducted by ORI in its oversight review, ORI found that  Takao Takahashi, MD, PhD, currently a faculty member in the Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu, Japan, and formerly a Visiting Scientist in the Hamon Center for Therapeutic Oncology Research, UT Southwestern, engaged in research misconduct in research supported by grant U01 CA084971.

ORI found that Respondent knowingly, intentionally, and recklessly falsified data reported in 4 publications:

  1. Takahashi, T., Shivapurkar, N., Reddy, J., Shigematsu, H., Miyajima, K., Suzuki, M., Toyooka, S., Zöchbauer-Müeller, S., Drach, J., Parikh, G., Zheng, Y., Feng, Z., Kroft, S.H., Timmons, C., McKenna, R.W., & Gazdar, A.F. “DNA methylation profiles of lymphoid and hematopoietic malignancies.” Clin Cancer Res. 10(9):2928-35, 2004 May 1 (hereafter referred to as “CCR 2004”); Retraction in: Clin Cancer Res. 19(1):307, 2013 Jan 1
  2. Takahashi, T., Suzuki, M., Shigematsu, H., Shivapurkar, N., Echebiri, C., Nomura, M., Stastny, V., Augustus, M., Wu, C.W., Wistuba, I.I., Meltzer, S.J., & Gazdar, A.F. “Aberrant methylation of Reprimo n human malignancies.” Int J Cancer 115(4):503-10, 2005 Jul 1 (hereafter referred to as “IJC 2005”); Retraction in: Int J. Cancer 132(2):498, 2013, Jan 15
  3. Takahashi, T., Shigematsu, H., Shivapurkar, N., Reddy, J., Zheng, Y., Feng, Z., Suzuki, M., Noomura, M., Augustus, M., Yin, J., Meltzer, S.J., & Gazdar, A.F. “Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers.” Int J Cancer 118(4):924-31, 2006 Feb 15 (hereafter referred to as “IJC 2006”); Retraction in: Int J Cancer 132(2):499, 2013 Jan 15
  4. Tokuyama, Y., Takahashi, T., Okumura, N., Nonaka, K., Kawaguchi, Y., Yamaguchi, K., Osada, S., Gazdar, A., & Yoshida, K. “Aberrant methylation of heparan sulfate glucosamine 3-O-sulfotransferase 2 genes as a biomarker in colorectal cancer.” Anticancer Res. 30(12):4811-8, 2010 Dec (hereafter referred to as “AR 2010”); Retraction in: Anticancer Res. 32(11):5138, 2012 Nov.

Respondent falsified data representing glyceraldehyde 3-phosphate dehydrogenase (GAPDH) loading controls and methylated/unmethylated PCR in RT-PCR gel panels.

Specifically, ORI found by a preponderance of the evidence that Respondent engaged in research misconduct by knowingly, intentionally, and recklessly falsely reporting the results of RT-PCR experiments by:

1. Reusing and relabeling an image and claiming it represents different experiments of human tumor cell lines subjected to different treatments; specifically, an identical image was used to represent the:

(a) GAPDH RT-PCR panels of several lymphoma, leukemia, multiple myeloma, and colorectal cancer cell lines in CCR 2004, Figures 1A and 1B, IJC 2005, Figure 1A, IJC 2006, Figures 1A and 2A, and AR 2010, Figure 1A

(b) GAPDH RT-PCR panels of the lymphoma cell lines BC-1 and Raji in CCR 2004, Figure 1B, lanes 1-3, and the colorectal cancer cell lines HCT116 and COLO201 in AR 2010, Figure 1C, lanes 4-6

(c) unmethylated form of p16 (p16UM) controls in the methylation-specific PCR (MSP) panels for the leukemia and multiple myeloma samples in CCR 2004, Figure 2

(d) p16UM MSP panels for the lymphoma and leukemia samples in CCR 2004, Figure 2, and the unmethylated bands MSP panel for the colorectal cancer (CRC) cell line in IJC 2005, Figure 5.

2. Manipulating an image and claiming it represents a gel with contiguous lanes; specifically, the RT-PCR products in the lanes of gels were cropped, spliced, and pasted together to form a single image for the MSP panels in IJC 2006, Figure 3.

Dr. Takahashi has entered into a Voluntary Settlement Agreement and has voluntarily agreed for a period of 3 years, beginning on August 26, 2014:

(1) To have his research supervised; Respondent agrees that prior to the submission of an application for U.S. PHS support for a research project on which the Respondent’s participation is proposed and prior to Respondent’s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondent’s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondent’s research; Respondent agrees that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agrees to maintain responsibility for compliance with the agreed upon supervision plan;

(2) that any institution employing him shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and

(3) to exclude himself voluntarily 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.


Notice is hereby given that ORI has taken final action in the following case:

Based on the report of an investigation conducted by UT Southwestern and analysis conducted by ORI in its oversight review, ORI found that Makoto Suzuki, MD, currently a Professor in the Department of Thoracic Surgery, Kumamoto University Hospital, Kumamoto, Japan, and formerly a Visiting Scientist in the Hamon Center for Therapeutic Oncology Research, UT Southwestern, engaged in research misconduct in research supported by grants P50 CA070907 and U01 CA084971.

ORI found that Respondent knowingly, intentionally, and recklessly falsified data reported in 6 publications:

  1. Suzuki, M., Hao, C., Takahashi, T., Shigematsu, H., Shivapurkar, N., Sathyanarayana, U.G., Iizasa, T., Fujisawa, T., Hiroshima, K., & Gazdar, A.F. “Aberrant methylation of SPARC in human lung cancers.” Br J Cancer 92(5):942-8, 2005 Mar 14 (hereafter referred to as “BJC 2005-1”); Retraction in: Br J Cancer 108(3):744, 2013 Feb 19
  2. Suzuki, M., Shigematsu, H., Shames, D.S., Sunaga, N., Takahashi, T., Shivapurkar, N., Iizasa, T., Frankel, E.P., Minna, J.D., Fujisawa, T., & Gazdar, A.F. “DNA methylation associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers.” Br J Cancer 93(9):1029-37, 2005 Oct 31 (hereafter referred to as “BJC 2005-2”); Retraction in: Br J Cancer 109(12)3132, 2013 Dec 10
  3. Suzuki, M., Shigematsu, H., Takahashi, T., Shivapurkar, N., Sathyanarayana, U.G., Iizasa, T., Fujisawa, T., & Gazdar, A.F. “Aberrant methylation of Reprimo in lung cancer.” Lung Cancer 47(3):309-14; 2005 Mar (hereafter referred to as “LC 2005”); Retraction in: Lung Cancer 85(2):337, 2014 August
  4. Suzuki, M., Toyooka, S., Shivapurkar, N., Shigematsu, H., Miyajima, K., Takahashi, T., Stastny, V., Zern, A.L., Fujisawa, T., Pass, H.I., Carbone, M., & Gazdar, A.F. “Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection.” Oncogene 24(7):1302-8, 2005 Feb 10 (hereafter referred to as “ONC 2005”); Retraction in: Oncogene 33(21):2814, 2014 May 22
  5. Suzuki, M., Shigematsu, H., Shivapurkar, N., Reddy, J., Miyajima, K., Takahashi, T., Gazdar, A.F., & Frenkel, E.P. “Methylation of apoptosis related genes in the pathogenesis and prognosis of prostate cancer.” Cancer Lett. 242(2):222-30, 2006 Oct 28 (hereafter referred to as “CL 2006”)
  6. Suzuki, M., Shigematsu, H., Shames, D.S., Sunaga, N., Takahashi, T., Shivapurkar, N., Iizasa, T., Minna, J.D., Fujisawa, T., & Gazdar, A.F. “Methylation and gene silencing of the Ras-related GTPase gene in lung and breast cancers.” Ann Surg Oncol. 14(4):1397-404, 2007 Apr (hereafter referred to as “ASO 2007”).

Respondent falsified data representing GAPDH loading controls and methylated/unmethylated PCR in RT-PCR gel panels.

Specifically, ORI found by a preponderance of the evidence that Respondent engaged in research misconduct by knowingly, intentionally, and recklessly falsely reporting the results of RT-PCR experiments by:

1. Reusing and relabeling an image and claiming it represents different experiments of human tumor cell lines subjected to different treatments; specifically, an identical image was used to represent the:

(a) GAPDH RT-PCR panels in BJC 2005-01, Figure 1A, lanes 4-12, and Figure 1C, lanes 4-12

(b) GAPDH RT-PCR panels in BJC 2005-2, Figures 1A and 1B, and ASO 2007, Figures 1A and 1B

(c) unmethylated form of p16 (p16U) RT-PCR panel in CL 2006, Figure 1, lanes 3-10, positive and negative controls, and the p16 U RT-PCR panel in ONC 2005, Figure 2A.

2. Manipulating an image and claiming it represents a gel with contiguous lanes; specifically, the RT-PCR products in the lanes of gels were cropped, spliced, and pasted together to form a single image for the:

(a) GAPDH RT-PCR panels in LC 2005, Figures 1A and 1B

(b) methylated form of Decoy receptor 2 MSP panel in CL 2006, Figure 1

(c) methylated form of small Ras-related GTPase MSP panel in ASO 2007, Figure 3B.

Dr. Suzuki has entered into a Voluntary Settlement Agreement and has voluntarily agreed for a period of 3 years, beginning on August 26, 2014:

(1) To have his research supervised; Respondent agrees that prior to the submission of an application for U.S. PHS support for a research project on which the Respondent’s participation is proposed and prior to Respondent’s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondent’s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondent’s research; Respondent agrees that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agrees to maintain responsibility for compliance with the agreed upon supervision plan;

(2) that any institution employing him shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and

(3) to exclude himself voluntarily 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.

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Findings of Research Misconduct x4

Today’s quartet …

Notice is hereby given that ORI has taken final action in the following case:

Based on an investigation conducted by Harvard Medical School and Beth Israel Deaconess Medical Center and additional analysis conducted by ORI in its oversight review, ORI found that Helen Freeman, PhD, former HMS Postdoctoral Fellow at BIDMS, engaged in research misconduct in research supported
by R37 DK053477.

ORI found that the Respondent engaged in research misconduct by knowingly and intentionally falsifying 3 figures and/or legends and 1 supplemental movie legend in a manuscript submitted for publication to the journal Nature (Freeman, H.C., Kong, D., Sidman, R.L., & Lowell, B. “Inhibition of UCP2 Prevents Neurodegenerative Diseases in Mice’). Specifically, ORI found that Respondent:

  • falsified Figure 6 and its legend in a manuscript submitted to Nature by claiming that the experiment represented histological and rotarod results from 5 week old pcd3J-/- mice treated with saline or pcd3J-/- mice treated with genipin when the genotype, treatment conditions, numbers of mice used, and mice age were not as claimed; these falsified data also were presented to a colleague for use in related experiments
  • falsified Figure 4, Supplementary Figure 3, and Supplementary Movie 1 and/or its legends in a manuscript submitted to Nature by claiming that the knockout of UCP2 rescues the ataxic phenotype of pcd3J-/- mice when she knew this to be false.

Dr. Freeman has voluntarily agreed for a period of 3 years, beginning on May 6, 2014:

(1) To have her research supervised if employed by an institution that receives or applies for U.S. PHS funding; Respondent agreed that prior to the submission of an application for PHS support for a research project on which the Respondent’s participation is proposed and prior to Respondent’s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondent’s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondent’s research contribution; Respondent agreed that she shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agreed to maintain responsibility for compliance with the agreed-upon supervision plan;

(2) that any institution employing her shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and

(3) to exclude herself voluntarily 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.

***

Notice is hereby given that ORI has taken final action in the following case:

Based on the reports of investigations conducted by Harvard Medical School and Fred Hutchinson Cancer Research Center and additional analysis conducted by ORI in its oversight review, ORI found that Zhihua Zou, PhD, former Postdoctoral Fellow, Department of Neurobiology, HMS, and former Staff Scientist, Division of Basic Sciences, FHCRC, engaged in research misconduct in research supported by R01 DC001622 and R01 DC004842.

ORI found that Respondent engaged in research misconduct by falsifying data that were included in 2 publications:

1. Zou, Z., Horowitz, L.F., Montmayeur, J.P., Snapper, S., & Buck, L.B. “Genetic tracing reveals a stereotyped sensory map in the olfactory cortex.’ Nature 414:173-179, 2001 (hereafter referred to as “Nature 2001′).

2. Zou, Z., Li, F., & Buck, L.B. “Odor maps in the olfactory cortex.’ Proc Natl Acad Sci USA 102:7724-7729, 2005 (hereafter referred to as “PNAS 2005′).

As a result of the investigations, both publications have been retracted.

Specifically, ORI finds that Respondent:

Falsified Figures 2k, 2l, 3a, 3f, 3h, and 3i in Nature 2001 and Figure 5C(b) in PNAS 2005 by manipulating the images to alter the number and location of positively stained cells in the olfactory bulb and olfactory cortex of mice.

Dr. Zou has entered into a Voluntary Settlement Agreement and has voluntarily agreed for a period of 3 years, beginning on July 9, 2014:

(1) That the administrative actions delineated in (2)-(4) below will be required for 3 years after the effective date of the Agreement, beginning on the date of Respondent’s employment in a research position in which he receives or applies for U.S. PHS support; however, if within 3 years of the effective date of the Agreement, Respondent has not obtained employment in a research position in which he receives or applies for PHS support, the administrative actions in (2)-(4) will no longer apply;

(2) to have any PHS-supported research supervised; Respondent agrees that prior to the submission of an application for PHS support for a research project on which the Respondent’s participation is proposed and prior to Respondent’s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondent’s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondent’s research; Respondent agrees that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agrees to maintain responsibility for compliance with the agreed upon supervision plan;

(3) that any institution employing him shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and

(4) to exclude himself voluntarily 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.

***

Notice is hereby given that ORI has taken final action in the following case:

Based on the Respondent’s admission, the report of an inquiry conducted by the University of Texas MD Anderson Cancer Center, and analysis conducted by ORI in its oversight review, ORI found that Dr. Jun Fu, PhD former Postdoctoral Fellow, Department of Neuro-Oncology, MDACC, engaged in research misconduct in research supported by CA56041 and CA127001.

The Respondent has admitted to knowingly and intentionally falsifying Figure 8a in the following publication:

“Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells.’ Cancer Res. 73(10):3062-74, 2013 May 15.

Specifically, the Respondent falsified survival times of mice to show that NVP-HSP990 prolonged survival rates in glioblastoma tumor bearing mice when experimental data were incomplete and unusable.

As a result of its inquiry, MDACC has recommended that the senior author of this paper take any appropriate steps with the journal to correct the scientific literature.

Dr. Fu has entered into a Voluntary Settlement Agreement (Agreement) and has voluntarily agreed for a period of 2 years, beginning on July 15, 2014:

(1) To have his research supervised; Respondent agrees that prior to the submission of an application for U.S. PHS support for a research project on which the Respondent’s participation is proposed and prior to Respondent’s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondent’s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondent’s research; Respondent agrees that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agrees to maintain responsibility for compliance with the agreed upon supervision plan;

(2) that any institution employing him shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and

(3) to exclude himself voluntarily 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.

***

Notice is hereby given that ORI has taken final action in the following case:

Based on the report of an investigation conducted by Southern Research Institute and additional analysis conducted by ORI in its oversight review, ORI found that Ms. Melanie Cokonis, former Research Technician, SRI, engaged in research misconduct in research supported by contracts N01-AI-30047 (HHSN2722011000009C) and N01-AI-70042 (HHSN272200700042C) and grant U54 HG005034.

ORI found that the Respondent engaged in research misconduct by falsifying assay data that were submitted in reports to NIH. Specifically, ORI found that Respondent knowingly falsified data for cytoprotection assays with antiviral compounds and provided the false data for inclusion in reports submitted to NIH for contracts N01-AI-30047 and N01-AI-70042 and grant U54 HG005034. Respondent transferred raw data from 8X12 SoftmaxPro matrix files into spreadsheets and then falsified the numbers for cell control, virus control, drug cytotoxicity, drug only, and/or cells+ virus+ drug wells to make 206 assays appear to have been successfully performed when they were not.

Ms. Cokonis has voluntarily agreed for a period of 3 years, beginning on May 29, 2014:

(1) To exclude herself from any contracting or subcontracting with any agency of the United States Government and from eligibility or involvement in nonprocurement programs of the United States Government referred to as “covered transactions’ pursuant to HHS’ Implementation (2 CFR part 376 et seq) of OMB Guidelines to Agencies on Governmentwide Debarment and Suspension, 2 CFR part 180 (collectively the “Debarment Regulations’); and

(2) To exclude herself voluntarily 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.

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Looking all the way ahead to FY16 …

Even though the upcoming Aug-Dec NIH deadlines will likely experience a higher number of applications due to the recent change in policy allowing unlimited resubmission of unfunded applications, you may want to be part of this crowded field since it is the last chance (aside from select PARs and RFAs) to be considered for FY15 funding.

Why is this important?

You may recall that the Budget Control Act of 2011 imposed caps on defense and non-defense discretionary spending plus a formula for sequestering funds to prevent deficit spending from FY13-FY21 in exchange for raising the debt ceiling. These caps resulted in the need to sequester funds from the budget, starting with 8% in FY13.

At the last possible moment, the Taxpayer Relief Act of 2012 delayed the FY13 sequester by 2 months and lowered the FY14 cap further to offset this delay, but FY13 was a rough year.

Then in December, the Bipartisan Budget Act of 2013 raised the non-defense discretionary spending caps for FY14 (from $472B to $491.8B) and FY15 (from $483B to $492.4B). However, it also extended the duration over which discretionary spending caps would be imposed from FY21 through FY23.

Congress is now working (or not) on the FY15 budget, which probably will not be known until well after the Oct 1 start date (necessitating a continuing resolution), and most likely will not be known until well after the mid-term elections, but the FY15 cap will have room to provide slightly higher appropriation levels than in FY14.

Although neither the House nor the Senate has moved an HHS appropriation bill for FY15 out of Committee, the Senate Appropriations Subcommittee mark-up bill for Labor, Health & Human Services, and Education currently allocates $30.46B to the NIH (increase of $606M, though $100M of this goes to the BRAIN initiative). The Subcommittee notes that “This level is sufficient, when combined with the $1M increase appropriated in FY14, to fully replace the FY13 sequester cut to NIH”. Not that we should be excited about being back where we should have been 2 years ago.

However, unless Congress passes additional legislation to provide relief from sequestration, the caps and potential cuts set for FY16-23 will remain in place.

Right now, the non-defense discretionary spending cap is at ~$493M for FY16 (same as FY15), though the Ryan budget drops this down to $450M (to eliminate any cuts to defense discretionary spending). Departments are not required to apply across-the-board cuts to remain within this cap, but for the NIH to be spared, another agency would need to be cut more severely. Think of HHS as a professional sports team with a salary cap: to fully fund the NIH, another program in Labor, HHS, or Education would need to come off the roster.

We have no idea what will happen in FY16 right now, especially with the midterm elections coming up. The Office of Management & Budget is currently asking all federal agencies to reduce their FY16 discretionary budget requests by 2% from the FY15 allocation.

So, to hedge your bets, you might want to get an application submitted for consideration in FY15. Also, please lobby your Congressional delegation (& please vote if you are eligible to do so) to be sure the NIH feels the love when they start negotiating whose appropriation is cut by how much under whatever spending cap is in place.

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Findings of Research Misconduct

Two rather different cases …

Notice is hereby given that ORI has taken final action in the following case: Based on an investigation conducted by Advocate Health Care Network d/b/a Advocate Health Care (Advocate Health Care) and additional analysis conducted by ORI in its oversight review, ORI and Advocate Health Care found that Parag Patel, DO engaged in research misconduct in research supported by  grant U01 HL089458.

ORI and Advocate Health Care found that the Respondent engaged in research misconduct by directing or intimidating fellows and others to influence left ventricular ejection fraction (LVEF) scores of <= 35% and requesting attending physicians to reassess scores of LVEF to be reported as <= 35% for research subjects after being diagnosed with acute myocardial infarction, thereby causing and being responsible for falsification of research records. These falsifications made subjects eligible for enrollment into the Vest Prevention of Early Sudden Death Trial (VEST) when they otherwise may not have been eligible.

The Respondent, Advocate Health Care, and the U.S. DHHS want to conclude this matter without further expenditure of time or other resources and have entered into a Voluntary Settlement Agreement (Agreement) to resolve this matter. Respondent neither admits nor denies ORI’s and Advocate Health Care’s findings of research misconduct. This settlement does not constitute an admission of liability on the part of the Respondent.

Dr. Patel has voluntarily agreed for a period of 2 years, beginning on February 21, 2014:

(1) To have any U.S. Public Health Service (PHS)-supported research in which he is involved be supervised; Respondent agreed that prior to the submission of an application for PHS support for a research project on which the Respondent’s participation is proposed and prior to Respondent’s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondent’s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondent’s research contribution as outlined below; Respondent agreed that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agreed to maintain responsibility for compliance with the agreed-upon supervision plan;

(2) That the requirements for Respondent’s supervision plan are as follows: A committee of 2-3 qualified physicians at the institution’s discretion, who are familiar with Respondent’s field of research, but not including Respondent’s supervisor or collaborators, will provide oversight and guidance; the committee will review primary data from Respondent’s participation in PHS-supported research on a quarterly basis and submit a report to ORI at 6 month intervals setting forth the committee’s meeting dates, Respondent’s compliance with appropriate research standards, and confirming the integrity of Respondent’s research contribution; and The committee will conduct an advance review of any PHS grant applications (including supplements, resubmissions, etc.), manuscripts reporting PHS-funded research submitted for publication, and abstracts; the review will include a discussion with Respondent of the primary data represented in those documents and will include a certification to ORI that the data presented in the proposed application/publication are supported by the research record; (3) That any institution employing him shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and (4) To exclude himself voluntarily 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.

***

Notice is hereby given that ORI has taken final action in the following case: Based on evidence and findings of an investigation report by Mount Sinai School of Medicine (MSSM) transmitted to ORI in April 2010 and additional analysis conducted by ORI in its oversight review, ORI found that Li Chen, PhD, former Postdoctoral Fellow, Department of Gene and Cell Medicine, engaged in research misconduct in research that was supported by grants R01 DK062972 and P20 GM075019 and was submitted in grant applications R01 DK074695, R01 DK083286, P20 GM075019, and R01 NS062054.

ORI found that the Respondent intentionally, knowingly, and recklessly fabricated and falsified data reported in 4 publications, 1 submitted manuscript, and 4 grant applications:

  • Chen, L., & Woo, S.L.C. Complete and persistent phenotypic correction of phenylketonuria in mice by site-specific genome integration of murine phenylalanine hydroxylase cDNA. Proc. Natl. Acad. Sci. U.S.A. 102(43):15581-15586, October 2005 (hereafter referred to as PNAS 2005).
  • Chen, L., Thung, S.N., & Woo, S.L.C. Metabolic Basis of Sexual Dimorphism in PKU Mice After Genome-targeted PAH Gene Therapy. Mol. Ther. 15:1079-1085, June 2007; Retracted in December 2010 (hereafter referred to as Mol. Ther. June 2007).
  • Chen, L., & Woo, S.L.C. Correction in Female PKU Mice by Repeated Administration of mPAH cDNA Using phiBT1 Integration System. Mol. Ther. 15:1789-1795, October 2007; Retracted in December 2010 (hereafter referred to as Mol. Ther. Oct. 2007).
  • Chen, L., & Woo, S.L.C. Site-Specific Transgene Integration in the Human Genome Catalyzed by [Ouml]BT1 Phage Integrase. Hum. Gene Ther. 19:143-151, February 2008; Retracted in August 2010 (hereafter referred to as HGT 2008).
  • Chen, L., Roy, I., Prasad, P.N., & Woo, S.L.C. Nanoparticle-Based Gene Therapy for Metabolic Disorders: Hepatic Delivery of Minicircle DNA for Complete Correction of Phenylketonuria. Submitted for publication in Proc. Natl. Acad. Sci. U.S.A. (hereafter referred to as the PNAS 2008 manuscript).
  • R01 DK074695, “Genome-targeted PAH Gene Integration in PKU Mice and Sexual Dimorphism,’ Savio L.C. Wood, PhD, PI
  • P20 GM075019, “Growth, Differentiation & Genetic Alteration of Human ES Cells,’ Gordon M. Keller, PhD, PI
  • R01 NS062054, “Nanoparticle-medicated Gene Therapy for PKU,’ Savio L. Woo, PhD, PI
  • R01 DK083285, “Nanoparticle-Mediated Gene Therapy PKU,’ Savio L. Woo, PhD, PI

The Respondent fabricated figures reporting the chromosomal locations of integration sites, fabricated data reporting the use of PCR to determine integration frequencies, falsified data representing the detection of chromosomal translocations in human cells, and fabricated figures by falsely reporting the results of HPLC assays. The Respondent also falsified experimental data for LacZ stained liver sections and for H&E stained liver sections.

Specifically, ORI finds by a preponderance of the evidence that the Respondent engaged in misconduct in science and research misconduct by intentionally, knowingly, and recklessly:

1. fabricating and/or falsifying 19 figures by falsely reporting that PKU gene therapy experiments were successfully completed, when the available evidence shows the experiments were not performed; specifically the Respondent:

(a) fabricated figures where DNA sequencing was purportedly used to identify the chromosomal locations of integration sites for the PAH gene in mouse and human cells, reported in 7 figures:

  • PNAS 2005, Figure 2A
  • HGT 2008, Figures 3b and 3c
  • R01 NS062054, Figures 3 and 20
  • R01 DK074695, Figure 6
  • R01 DK083286, Figure 17
  • P20 GM075019, Figure 4

(b) fabricated data purportedly representing the use of PCR to determine integration frequencies for the PAH gene and the secreted embryonic alkaline phosphatase (SEAP) reporter gene, in mouse and human cells, reported in 11 figures:

  • PNAS 2005, Figures 2C and 3B
  • Mol. Ther. June 2007, Figures 2a and 5a
  • Mol. Ther. Oct. 2007, Figures 2d and 5a
  • HGT 2008, Figure 4 R01 NS062054, Figures 4b and 10a
  • R01 DK074695, Figure 7b
  • R01 DK083286, Figure 2b

(c) falsified figures representing the detection of chromosomal tranlocations in human cells, purportedly determined by PCR in 2 figures:

  • HGT 2008, Figure 5a
  • R01 NS062054, Figure 21a

2. fabricating the results of HPLC assays to show generally lowered blood levels of phenylalanine after PKU gene therapy and to show liver levels of BH4 when the Respondent did not have the HPLC data needed to support those claims; specifically the Respondent:

(a) fabricated serum phenylalanine graphs in:

  • PNAS 2005, Figure 4B; this false data also is presented in R01 DK074695, Figure 10b
  • Mol. Ther. June 2007, Figure 1a; this false data also is presented in R01 DK074695, Figure 11
  • R01 DK083286, Figure 3; this false data also is presented in Mol. Ther. June 2007, Figure 3, and R01 NS062054, Figure 7
  • Mol. Ther. Oct. 2007, Figure 4a; this false data also is presented in R01 NS062054, Figure 9a
  • PNAS 2008 manuscript, Figure 4

(b) fabricated graphs for BH4 levels in:

  • Mol. Ther. June 2007, Figure 5c; this false data also is presented in R01 NS062054, Figure 8c

3. falsely reporting the results of LacZ stained liver sections by reusing and relabeling an image and claiming that it represents different experiments; specifically, the same image was used to represent mice treated with a nanoplex gene delivery system in R01 NS062054, Figure 14b (right panel), and also to represent a wholly different experiment for mice treated with 10 injections of the phiBT1 integrase system alone in R01 NS062054, Figure 4c (right panel), and Mol. Ther. Oct. 2007, Figure 2b (D panel)

4. falsely reporting the results of H&E stained liver sections in R01 NS062054, Figure 6, by using the identical image to represent 4 different experimental treatments of H&E stained liver sections; specifically the Respondent reused and relabeled one image to represent liver sections from mice that received either 1 or 10 injections, with or without the phiBT1 integrase plasmid.

The Respondent failed to take responsibility for the fabrication and falsification described in ORI’s findings.

The following administrative actions have been implemented for a period of 3 years, beginning on April 11, 2014:

(1) Respondent is debarred from any contracting or subcontracting with any agency of the United States Government and from eligibility for, or involvement in, nonprocurement programs of the United States Government referred to as “covered transactions’ pursuant to HHS’ Implementation (2 CFR part 376 et seq.) of Office of Management and Budget (OMB) Guidelines to Agencies on Governmentwide Debarment and Suspension, 2 CFR part 180 (collectively the “Debarment Regulations’); and

(2) Respondent is prohibited 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.

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NIH Fairy Grants Your Wish for Unlimited A0s

In a new Notice, the NIH went beyond reversing its decision to eliminate the A2 submission to allow, in theory, unlimited A0 submissions of the same proposal (hopefully improved with each submission).

Effective immediately, the NIH and AHRQ will accept a new (A0) application following an unsuccessful resubmission (A1) application. The subsequent new application need not demonstrate substantial changes in scientific direction compared to previously reviewed submissions, and must not contain an introduction to respond to the critiques from the previous review.

Although reviewers of this subsequent A0 might think it sounds familiar, they will not have the prior applications or summary statements and will be instructed to treat each A0 as new (and it will have a new grant number assigned).

The NIH and AHRQ will not assess the similarity of the science in the new (A0) application to any previously reviewed submission when accepting an application for review. Although a new (A0) application does not allow an introduction or responses to the previous reviews, the NIH and AHRQ encourage applicants to refine and strengthen all application submissions.

However, if it feels like Groundhog Day without hope of ever reaching Feb 3 or a competitive score, reviewers will also likely be encouraged to comment on unproductive repetitive submissions in the Additional Comments to Applicant.

Also, the new policy makes clear that PIs cannot resubmit the application as soon as they know their score and still cannot have overlapping proposals under review at the same time.

This means that the NIH will not review:

  • a new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping resubmission (A1) application.

  • a resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

  • an application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101). {writedit: yet another reason not to appeal}

PIs should communicate with their PO about resubmission strategy. An ND (not discussed) A0 might do better just going back as an A0 again (skipping a written introduction as an A1). If the PI would do better to write the introduction to clarify/highlight improvements based on the A0 discussion, then an A1 might be the more strategic submission (plus the extra month may be useful). A Type 2 (competing renewal) would need to go in as an A1 to remain under consideration as a Type 2 (if/when subsequently submitted as A0, becomes Type 1 again and loses the Progress Report and competing renewal submission date/status). Some FOAs will limit whether an application can be submitted as an A1, too. You should definitely talk with your PO for advice. There will also be FAQs issued [update: a new Notice provides some clarification].

This strategy should bypass the prior “getting in line” philosophy of the A0-A1-A2 progression while allowing PIs to continue refining, improving, and submitting proposals from their evolving research program. As the Notice notes, this should particularly help early career investigators who have not had the time or resources to begin developing parallel research programs attractive to different ICs and SRGs. Let the writing and rewriting begin.

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NIH FY15 Budget in Brief

The President made a friendly suggestion about how Congress might spend federal monies appropriated for FY15.

As shown in the Budget in Brief released by HHS, the additional $211M suggested for the NIH (bringing the appropriation to $30.4B) is not evenly distributed.

Winners include NIAID (+$31M), NCATS (+$25M), NIMH (+$23M), NINDS (+$23M), and NIDDK (+$12M).

The remaining increases are all single-digit millions, and while no IC lost funding, several received no increase in their appropriation above FY14: NIDCR, NIDCD, NINR, NIMHD, NCCAM, FIC.

Several more only get an additional $1M (i.e., an extra R01): NEI, NIA, NIAMS, NIAAA, NHGRI.

Over half (53.4%) the extra $211M goes toward RPGs – $120M – which the NIH estimates will translate into 9,326 new and competing awards (or 329 more grants than in FY14).

NIH estimates that it will spend $566M on Alzheimer’s disease research and more than $3B on HIV/AIDS research.

The NIH will devote $100M to the BRAIN initiative (up from $40M in FY14).

The Cures Acceleration Network appropriation jumps to $30M (up from $10M in FY14).

There will be a 2% increase in stipends for pre- and postdoctoral trainees supported by National Research Service Awards (Fs & Ts).

Intramural research increases by $39M from FY14 to $3.4B (11.3% of the NIH appropriation).

In the unlikely event that the proposed Opportunity, Growth, and Security Initiative comes to pass (i.e., President’s request for $56B above the Congressionally mandated cap on discretionary spending offset by higher tax revenues and other cuts), the NIH would receive an additional $970M.

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FY13 Funding Trends

In working on the book, I was disappointed that we could not get funding trend data for more ICs (10 of 24). Publishing the range of percentiles over which applications are scored versus funded allows applicants to see patterns of skipping awards at lower percentiles and how high an IC will go for select pay decisions. Even though seeing these charts does not affect the outcome of an individual application, some data are better than no data for overall mental health as well as application and career planning.

Here at MWEG, I have a page with links to available funding trend data, which I will update as new data show up at IC Websites.

Those with FY12 data online include NHLBI (success rate only), NIAAA (success rates only), NIAMS, NIGMS, and NINDS (NIAID has FY11 data). The book adds charts for NIA, NIDA, NIMH, and NIEHS (FY11 only). Success rate data (by IC, activity code, FY, etc.) can always be found at NIH RePORT.

FY13 funding trend data are now available from NCI and NIDDK.

NIDDK went down a couple points on its R01 payline (13/18 in FY12 down to 11/16 in FY13 for established/new-ESI), and they seem to be accommodating more new R01s at the expense of renewals and the amount spent per award. NIDDK covers all the award mechanisms and even breaks out Ks by activity code.

NCI focuses on R01s and R21s but does include some R03 and RFA data. Perhaps most interesting is the comparison of FY12 and FY13 success rate data:

—FY12:

  • —R01 unsolicited: 620 awards, 15% success rate
  • —R21 unsolicited: 200 awards, 11% success rate
  • —R03: 101 awards, 20% success rate
  • —RFAs: 88 awards, 9% success rate
  • —Total RPGs: 1085 awards, 14% success rate
—FY13:
  • —R01 unsolicited: 582 awards, 15% success rate
  • —R21 unsolicited: 241 awards, 10% success rate
  • —R03: 100 awards, 15% success rate
  • —RFAs: 82 awards, 16% success rate
  • —Total RPGs: 1095 awards, 14% success rate

Not sure whether the drop in RFA applications in FY13 is due to fewer RFAs issued or fewer applicants to the RFAs issued; it’s a little tricky to figure out by searching the Guide, since some RFAs have multiple receipt dates spanning FYs, and the Provocative Questions RFAs were broken out into 4 groups per activity code (so 8 FOAs covering same ground as 2 FOAs previously).

NCI also includes success rate data for new-ESI applicants for both the R01 and R21 activity codes. Only applicants to the R01 are given special consideration at review and award time, and the data confirm this: the success rate for new/ESI applicants to the R01 activity code was 12% (18% for ESI – compared with 13% for new applications from experienced PIs) versus 8% for R21s (experienced PIs stayed at 13%).

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