Dr. John Kauwe, Department of Biology

Project Justification and Overview

Successful enrollment in and completion of graduate programs requires a constellation of skills. Students must be prepared to plan and execute experiments, present their findings both verbally and in manuscript form and interact effectively with senior scientists in the field of their choice. In this Mentoring Environment Grant (MEG) I will mentor four undergraduate students, (David Patty, Matthew Bailey, *Iulianna Sambur and Mo Lee) as they develop skills in study design, data analysis, manuscript preparation, presentation and networking while identifying genetic factors that modulate protein levels and influence Alzheimer’s disease.

*Iulianna Sambur decided to change her major just before the MEG was funded and was replaced by David Peterson.

Evaluation of Academic Objectives

This MEG was proposed with specific objectives associated with a five phase mentoring plan.

Phase 1

In Phase 1 students in the MEG group will receive training in data management and analysis.

Phase 1 Benchmarks:

• Each student in the MEG group will prepare an ORCA proposal based on his or her training project.

Progress:

• All four students in the MEG group submitted ORCA proposals.

Phase 2

In Phase 2 the students will evaluate their respective biomarker dataset(s) and design their studies.

Phase 2 Benchmarks:

• Participation in weekly MEG group meetings
• Leadership in the design of the study to be authored by the student
• Submission of ORCA peer reviews
• Submission of an ORCA grant proposal

Progress:
Weekly meetings MEG group meetings were held throughout the year. Students successfully outlined study plans and drafted proposals for analysis. Students reviewed each other’s proposals and provided critical peer evaluations. All four students in the MEG group submitted ORCA proposals. The ORCA proposals from David Patty, David Peterson and Mo Lee were funded.

Phase 3

In phase 3 students will execute their analysis plan, draft their manuscript and prepare a presentation for a scientific meeting (the meeting may vary by student as appropriate).

Phase 3 Benchmarks:

• Submission of an abstract for the appropriate scientific meeting
• Draft manuscript describing findings

Progress:
All four students executed their analysis plans. David Patty, David Peterson and Matthew Bailey successfully submitted abstracts to the International Conference on Alzheimer’s Disease. These students are currently drafting manuscripts. Mo Lee’s co-authored a paper entitled, “Fine Mapping of Genetic Variants in BIN1, CLU, CR1 and PICALM for Association with Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease,” which was published in PLoS ONE.

Phase 4

In Phase 4 students will begin preparations to attend the GAW meeting and participate in the group discussion of their respective analyses.

Phase 4 Benchmarks:

• Acceptance of the abstract to the scientific meeting
• Successful presentation and participation in the scientific meeting
• Establish contact with at least one potential mentor outside of BYU

Progress:

David Patty, David Peterson and Matthew Bailey each had their abstracts accepted for poster presentations and the International Conference on Alzheimer’s disease. In addition, David Patty and Matthew Bailey received Travel Fellowships to attend the meeting. Their presentations were spectacular and several colleagues expressed their surprise that my students were undergraduates. Each student made multiple, personal connections with future mentors. Specifically, David Peterson initiated relationships with Alison Goate of Washington University, Paul Crane of the University of Washington, and Peter Zandi of John Hopkins University. David Patty and Matthew Bailey initiated relationships with Drs. Goate and Carlos Cruchaga from Washington University and Dr. Ryan Watts, Associate Director of Neurodegeneration Labs at Genentech.

Phase 5

In phase 5 students will incorporate what they learned at the scientific meeting, revise their manuscripts and submit them to a peer-reviewed journal.

Phase 5 Benchmarks:

• Submission of manuscript for peer review
• Acceptance/Publication of a manuscript

Progress:

• Data analyzed during this grant period has resulted in three manuscripts; one is published, one is in press, the others are in preparation.

Assessment of the Mentoring Environment

The vast majority of the pre-established benchmarks for this training program were met. This presents a very positive assessment of the mentoring environment. I have solicited comments from my students for a qualitative assessment of the environment. The following are their unedited responses to my request that they send a “paragraph discussing what you learned over the past year and how (or if) the mentoring environment enriched your education”:

Mo Lee: “I always enjoy working in the Kauwe lab. In the lab, we have great computational resources that allow us to carry out quality genetic analyses on our huge data sets from ADNI or Washington University in St. Louis. The environment and the people in the lab are simply awesome. Doctor Kauwe is always very willing to help us, and he cares for us not just on our academic performance but also on other aspects of life. This summer, I was able to go on an internship called BioMedRap at Washington University in St. Louis. With the sufficient and solid training I had in the lab for the past 2 years, I was able to be at the top niche in internship and got more out of it. As an international student from Taiwan, Doctor Kauwe was always able to make my life easier. I spent one Thanksgiving with his family, and we had Lab Christmas party every year. He really has helped me to understand that science can be really fun and how to love science. Students in the lab always help one another to learn better and faster. This is the best lab I have ever worked in because we have the best mentor and great students..”

David Patty: “Since joining the Kauwe lab, my understanding and appreciation for science has multiplied greatly. Dr. Kauwe gives his students invaluable guidance on getting into a graduate program, such as where to apply, what is needed to be competitive, and how to be successful as an undergraduate student. He introduces us to faculty and colleagues from different universities. His help on the presentation of ideas, construction and review of papers, submitted grant proposals, scientific posters, powerpoints has opened up a world of opportunity where we are ready and prepared to succeed. Dr. Kauwe created an environment where learning and academic achievement are important, and infused in his students a desire to do great things. He lets the students teach each other to more fully ingrain the principles of statistics, genetics, programming, and collaboration. He also emphasizes the importance of being ethical in our research. Overall I feel that I owe all of my current skills and knowledge and most of all my future successes to Dr. Kauwe. I give my highest recommendation for Dr. Kauwe to continue to be able to mentor undergraduate students. It is professors like Dr. Kauwe that you want to shape the future of academics and the workforce of tomorrow.”

David Peterson: “Being mentored in Dr. Kauwe’s lab has been an invaluable part to my education and preparation for medical school. As a research assistant in his lab I have had the opportunity to frequently receive personalized feedback and direction in a one-on-one setting. I have been able to not only participate in meaningful research, but to be an integral part of it. Dr. Kauwe trusts and empowers his students in a way that few other undergraduate research mentors do. I have been involved in experimental design, data collection and analysis, manuscript drafting, poster design, and presentation. I recently attended the International Conference on Alzheimer’s Disease in Paris France with Dr. Kauwe and two other undergraduate students where I was able to present relevant research on genetic factors that influence the rate of progression of Alzheimer’s disease. Few undergraduate students ever get to have the kinds of opportunities as I have had while being mentored in Dr. Kauwe’s lab. Dr. Kauwe is committed to the success of his students above all else, and I am confident that he will continue to help students accomplish their academic and career goals for years to come.”

Matthew Bailey: “Working in Dr. Kauwe’s lab for the last year has been a blast. I am a bioinformatics major with aspirations of obtaining a PhD. When I first entered the lab I had a minimal background in Java, and a desire to discover the scientific community. I will be leaving the lab with practical experience in a number of applicable software languages, such as C++, PLINK, Perl, Python, Linux, and SAS. Dr. Kauwe has helped me discover a number of fundamental scientific web-base programs such as NCBI (Nation Center for Biotechnology Information), dbGaP (The database of Genotypes and Phenotypes), and SNAP (SNP Annotation and Proxy Search), etc. I have sharpened my skills with EXCEL, UltraEdit, and PowerPoint in order that I may present our lab’s findings. This spring I had the opportunity to present at the BYU President’s Leadership Council where I informed substantial donors of our lab’s contribution to Alzheimer’s disease. This last year I have presented scientific posters at both the BYU Poster Session in Provo, and the International Conference on Alzheimer’s disease in Paris, France. This last summer I was accepted as a fellow to the BYU Cancer Research Center where I applied what I’ve learned this past year in genomic analytics of Alzheimer’s to a number of different cancers. Since being lab I have come to understand what it takes to set myself apart as a competitive applicant to graduate school, and with the help of Dr. Kauwe, I know I will measure up against the best.”

Participants/Academic Deliverables

Mo Lee:
Mo is the co-author of a paper entitled “Fine mapping of SNPs in BIN1, CLU, CR1 and PICALM for association with CSF biomarkers for Alzheimer’s disease”1, which was published in PLoSONE. She was also admitted to a prestigious summer research program (BioMedRAP) at the Washington University School of Medicine for the summer of 2011. Mo also received an ORCA Grant from BYU.

David Patty:
David co-authored a paper entitled, “Performances on the CogState and Standard Neuropsychological Batteries Among HIV Patients Without Dementia” which is in press in the journal AIDs and Behavior. He also received a Travel Fellowship to the International Conference on Alzheimer’s disease and was the first author and presenter of a poster at the conference. David also received an ORCA Grant from BYU.

David Peterson:
David is the co-author of a paper entitled, “Support for genetic association between variants in PPP3R1 and MAPT and rate of progression of Alzheimer’s disease: The Cache County Aging Study,” which is currently in preparation. He was the first author and presenter of a poster of the same title at the International Conference on Alzheimer’s disease. David also received an ORCA Grant from BYU.

Matthew Bailey:
Matthew is the co-author of a paper entitled, “Fine mapping of AD associated variants for association with cerebrospinal fluid biomarkers and neuropathological features,” which is currently in preparation. He presented this work at the BYU practice poster session. He also received a Travel Fellowship to the International Conference on Alzheimer’s disease and was the first author and presenter of a poster at the conference. In addition, he received a BYU Cancer Research Center Fellowship to support his efforts toward understanding the genetic control of cancer related cerebrospinal fluid protein levels. Matthew was also selected to represent the College of Life Sciences to the BYU President’s Leadership Council where he informed BYU supporters of our lab’s contribution to understanding Alzheimer’s disease.

Results/Findings of this Project

Data generation and analysis associated with this project provided the following conclusions:

1. Genetic variants in BIN1, CLU, CR1 and PICALM, which show association with risk for Alzheimer’s disease, do not appear to influence cerebrospinal fluid levels of two important biomarkers for Alzheimer’s disease.¹
2. We determined that a brief computerized battery correlates with formal neurocognitive testing. Specifically, 53% of the variance in the composite Global Deficit Score (formal neurocognitive testing) was accounted for by elements from the brief computerized tool (P < 0.01). Using the five significant parameters from computerized battery in a Receiver Operating Characteristic curve, 90% of persons could be accurately classified as being cognitively impaired or not.²
3. There is evidence of consistent effects on both CSF biomarker levels and neuropathological features by Alzheimer’s disease risk associated genetic variants.

Budget Summary

Funds from this MEG were used to fund salary for these undergraduates from Jan 2010 to present, to print posters and to fund their travel costs to the International Conference on Alzheimer’s disease. The funds from this MEG have been completely spent.

Summary

This MEG has successfully provided students with training in analysis of data currently being generated in the study of human genetics, exposure to and interaction with other scientists in a professional setting, experience in the presentation of primary data at a conference, and experience in writing, submission, review, revision and publication of manuscripts. The awards, honors and academic products associated with this MEG illustrate both the excellence of the undergraduates that were part of this grant and the quality of the mentoring environment in the Kauwe lab.

References:

1. “Fine Mapping of Genetic Variants in BIN1, CLU, CR1 and PICALM for Association with Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease” Kauwe JSK, Cruchaga C, Karch CM, Sadler B, *Lee M, Mayo K, Latu W, Su’a M, Fagan AM, Holtzman DM, Morris JC, ADNI and Goate AM. (2011). PLoS ONE 6:e15918.
2. “Performances on the CogState and Standard Neuropsychological Batteries Among HIV Patients Without Dementia” Overton ET, Kauwe JSK, Paul R, Tashima K, Tate DF, Pragna P, Carpenter CCJ, *Patty D, Brooks JT, Clifford DB. (2011) AIDS and Behavior In press.

*BYU Undergraduate mentored by Dr. Kauwe as part of this MEG