News

New Technique Can Help Researchers Explore the Rhythm of Genes

Oscope uncovers dynamic signals of technical origin in scRNA-seq data sets

MADISON, Wis. — Genetic cycles, from circadian rhythms to the cycles involved in reproduction, are everywhere. Now, a recent University of Wisconsin-Madison study is putting a new tool in the arsenal of researchers when it comes to the ebb and flow of gene expression. The new statistical approach, named Oscope, lets researchers identify and characterize the rhythm of genes across the entire genome using single-cell RNA sequencing.

Common genetic cycles include the circadian rhythm that regulates our behaviors over the 24-hour period and those that govern the division and multiplication of cells. Cycles are evident across almost all living systems, and errors in the process often lead to a variety of diseases. To study these cycles using traditional technologies, researchers must synchronize a whole population of cells so they are at the same state. Unfortunately, such synchronization isn’t possible for many cell types and conditions.

However, new RNA sequencing technology allows scientists to probe the genome wide expression of a single cell. When the cell is harvested for sequencing, it is destroyed in the process so it can’t be sequenced again to uncover an oscillating gene pattern. But with that single-cell information, researchers were able to ‘reorder’ unsynchronized cells and uncover a pattern of expression.

Oscillating gene expression can be thought of like a sine wave, moving up and down on a graph as the gene is expressed, repressed, and expressed again over time. Oscope uses a dataset from unsynchronized, single-cell RNA sequencing.

Christina Kendziorski, a professor of biostatistics and medical informatics at the UW School of Medicine and Public Health, led the team that developed Oscope to address the drawbacks of existing methods used to explore gene expression. The project melded the statistical strengths of the Kendziorski lab with the cell biology expertise from the lab of James Thomson, pioneer stem cell biologist at the UW and researcher at the Morgridge Institute for Research in Madison.

“This project is a great example of the collaborative efforts that are required to address the most challenging problems facing scientists today,” said Kendziorski.

Techniques to study oscillating gene expression in individual cells have existed for a long time. They include fluorescent tagging, where a certain gene is ‘tagged’ with a light-emitting molecule and gene expression is measured in proportion to the light emitted by the tag. If the tag is emitting light, the gene is active. However, this technique is labor-intensive and can only examine a handful of genes at a time.

When genetic rhythms are of interest across the entire genome, researchers often use traditional or bulk RNA sequencing, where a researcher examines the average gene expression over a large population of cells at various times. But to look at different times, the technique requires multiple populations of cells because the population is destroyed when expression is measured. The other issue here is the populations must be synchronized—starting and continuing at the same state of expression—which doesn’t always hold over time.

“After looking at average gene expression for over a decade, the ability to see genome-wide gene expression in individual cells is particularly exciting. Unfortunately, we only have a snapshot, and that’s the tricky part. We want to study oscillatory gene expression, but we don’t have time course data,” said Kendziorski, “so we developed a statistical method that would allow us to look at oscillatory genes and reconstruct one cycle of their oscillation that doesn’t involve time course experiments or synchronization.”

While the technique offers a new way to study gene oscillations, it does have limitations. The method can only reconstruct one cycle of the oscillation instead of its full oscillatory path. Another limitation is that with time course, one can see much more detailed dynamic for many genes.

Yet, for those working with oscillatory genes but uninterested in studying their rhythms, Oscope may be helpful in weeding out unnecessary data, letting a researcher adjust for the genetic variance that comes with oscillation, thereby improving the power to see the signal they’re most interested in.

This study was published in Nature Methods on August 24, 2015. The work was supported by US National Institutes of Health grants GM102756, 4UH3TR000506 and 5U01HL099773, the Charlotte Geyer Foundation and the Morgridge Institute for Research.

Professor Kim to present at Univeristat Autònoma de Barcelona

KyungMann Kim, Ph.D., Professor of Biostatistics and Statistics, has been
invited for a two-week (October 4-18) research visit to the Centre de Recerca
Matemàtica (CRM) located at the Universitat Autònoma de Barcelona as a Simons
Visiting Researcher. This will be Dr. Kim's second visit to the Universitat
Autònoma de Barcelona where he gave a two and a half day short course entitled
"Data and Safety Monitoring and Interim Analysis in Clinical Trials: Sequential
Methods" in June 2001.

The Simons Visiting Program is funded by the generous support of the
Mathematics and Physical Sciences branch of the Simons Foundation, the
Universitat Autònoma de Barcelona, and the Universitat Politècnica de
Catalunya, and its aim is to enhance the CRM Intensive Research Programme in
Statistical Advances for Complex Data.

Prof. Richard Chappell is 2015 AbbVie Statistics Visiting Scholar

Biostatistics and Medical Informatics Professor Rick Chappell has been named the 2015 AbbVie Statistics Visiting Scholar. In this role, Dr. Chappell will spend considerable time over the coming year in-house collaborating with AbbVie statisticians and other biopharmaceutical scientists on problems related to statistical design and analytical methodology needed to fully exploit information collected from AbbVie clinical trials. Whereas the primary focus will be on the design and analysis of AbbVie trials, from concept through analysis and reporting, Rick may also conduct seminars, engage in training and mentoring activities, and/or participate in the design of protocols or charter templates for novel types of clinical trials or other research. AbbVie (www.abbvie.com) is a global, research-based biopharmaceutical company situated in North Chicago.

Cook and Buhr Present Novel Course on Valid Clinical Trials

Senior Scientist Tom Cook and Associate Scientist Kevin Buhr, in collaboration with University of Utah Associate Professor Charlie Casper presented an evening workshop titled “Conducting Valid Trials: The Critical (and Misunderstood) Roles of Randomization and Complete Follow-Up” at the Society for Clinical Trials 36th Annual Meeting in Arlington, Virginia.

Randomized, double-blind clinical trials are widely considered the gold standard for establishing causal relationships between interventions and outcomes of interest. However, the importance of randomization and the intention-to-treat (ITT) principle in the design, conduct, and analysis of such trials — while widely recognized — is often not well understood. In this first-time SCT workshop, Cook and colleagues used easily understood models and examples, accessible to a non-mathematical audience, to demonstrate why randomization and ITT analysis lead directly to valid assessments of whether a new treatment “works”.

Despite some initial skepticism on the part of the Society's Education Committee, the workshop was very well received and sported the second highest attendance at the meeting. The presenters are planning to extend it to a longer morning workshop for next year's meeting.

The Society for Clinical Trials is an international professional organization dedicated to the development and dissemination of knowledge about the best practice in design, conduct, analysis and reporting of clinical trials with membership from government, academia, industry and non-profit organizations.

Associate Professor Menggang Yu Approved for over $1M Research Funding Award by the Patient-Centered Outcomes Research Institute

"The left panel represents a convex approximation for the 0-1 loss. In particular, the approximation is a surrogate logistic loss where the parameter "a" controls the shape of the surrogate. The right panel represents a non-convex approximation for the 0-1 loss where the parameter "a" controls the proximity of the surrogate."

Congratulations are in order to Associate Professor Menggang Yu for his imminent funding award from the Patient-Centered Outcomes Research Institute (PCORI) for his project entitled "Matching Complex Patients to Treatments: Innovative Statistical Scoring Methods for Treatment Selection". The project, which will run for 3 years, aims to develop and disseminate innovative statistical methods to rank possible treatments for patients according to their likelihood of achieving desirable patient outcomes. The ranking will be based on patient characteristics such as demographics and socio-economic variables, inpatient/outpatient diagnoses, comorbidity, pharmacy claims, health system and clinic information.

The award is one of four or five PCORI awards received recently by investigators at the University of Wisconsin School of Medicine and Public Health, and highlights the Department’s commitment to health services research.

The study is one of 46 proposals that PCORI approved for funding on Tuesday, April 21, to advance the field of comparative clinical effectiveness research (CER) and provide patients, healthcare providers, and other clinical decision makers with information that will help them make better-informed choices.
The award has been approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract to the University.

“This project was selected for PCORI funding not only for its scientific merit and commitment to engaging patients and other stakeholders, but also for its potential to fill an important gap in our health knowledge and give people information to help them weigh the effectiveness of their care options,” said PCORI Executive Director Joe Selby, MD, MPH. “We look forward to following the study’s progress and working with the University of Wisconsin School of Medicine and Public Health to share the results.”

Professor Yu’s study and the other projects approved for PCORI funding were selected through a highly competitive review process in which patients, clinicians, and other stakeholders joined clinical scientists to evaluate the proposals. Applications were assessed for scientific merit, how well they will engage patients and other stakeholders, and their methodological rigor among other criteria.

PCORI is an independent, non-profit organization authorized by Congress in 2010 to fund comparative clinical effectiveness research that will provide patients, their caregivers, and clinicians with the evidence-based information needed to make better-informed health and healthcare decisions. PCORI is committed to seeking input from a broad range of stakeholders to guide its work.

PCORI has approved $854 million to support 399 research studies and initiatives since it began funding research in 2012. For more information about PCORI funding, visit http://pcori.org.

KyungMann Kim Elected Vice President / President of International Society for Clinical Biostatistics

KyungMann Kim, Ph.D., Professor of Biostatistics and Statistics, Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, was recently elected as Vice President for 2015-2016 for the International Society for Clinical Biostatistics and will serve as President during 2017-2018 and Past President in 2019.

The International Society for Clinical Biostatistics (http://www.iscb.info) is an international organization founded in 1978 to stimulate research into the principles and methodology used in the design and analysis of clinical research studies and to increase the relevance of statistical methods and theory to the real world of clinical medicine. The primary activity of the Society is to organize an annual conference. This year’s annual conference, known as ISCB36 to mark the 36th annual conference of the Society, will be held in Utrecht, the Netherlands during August 23-27, 2015 (http://www.iscb2015.info).

Congratulations, KyungMann!

Roy Part of Team to Examine Toxins

BMI Asst. Prof. Sushmita Roy is part of a diverse new team of UW-Madison researchers who received $6 million from the U.S. Environmental Protection Agency to develop models and screening tools that will rapidly advance knowledge of the health effects of today's ever-growing assortment of environmental toxins. Awarded through the EPA Science to Achieve Results (STAR) program, the grant will create the Human Models for Analysis of Pathways (H-MAPs) Center at UW-Madison. See more: http://www.news.wisc.edu/23596

Korthauer Wins ENAR Poster Award

Congratulations to biostatistics PhD student Keegan Korthauer for garnering an ENAR RAB Poster Award at the recent meetings of the Eastern North American Region of the International Biometric Society in Miami, Florida. Keegan's poster is entitled "Differential dynamics in single-cell RNA-seq experiments", research conducted under the direction of BMI Professor Christina Kendziorski.

Congratulations Keegan and Christina!

Senior Scientist Thomas Cook to receive the 2015 Chancellor's Award for Excellence in Research

BMI Senior Scientist Thomas Cook has been selected to receive the 2015 Chancellor's Award for Excellence in Research as an Independent Investigator! He was one of nine honorees to receive an Academic Staff Excellence Award.
This designation is awarded to Tom for his deep and broad contributions to the conduct and analysis of clinical trials, both in applications and methodology development.

Tom has satisfied all of the Award criteria: "Outstanding achievement and performance by the candidate, [who] consistently and substantially exceeds the expectations of the position; has made important and significant contributions to the departmental unit; has furthered the mission of the university; and has become a distinguished member of his/her profession campus-wide, system wide, nationally, or internationally".
BMI Distinguished Scientist Marian Fisher spearheaded Tom's nomination and worked diligently to complete it with great attention to the details!

Congratulations, Tom and Marian!

David Page awarded a Kellett Mid-Career Faculty Researcher Award

Professor David Page has been awarded a Kellett Mid-Career Faculty Researcher Award for the period starting in July 2015 through June of 2020. This is a wonderful recognition by the University of David's broad and deep contributions to the research enterprise across the UW campus and beyond. The award recognizes his academic success and provides an opportunity for continued development of his outstanding research program.

The fellowship is named in honor of William R. Kellett, a WARF Trustee and President of the WARF board. A Wisconsin native, graduate of the College of Engineering and an enthusiastic supporter of the University, Kellett held an abiding commitment to the reform and progress of Wisconsin’s educational institutions.

Professor Jude Shavlik of Computer Sciences, with an affiliate appointment in Biostatistics and Medical Informatics, spearheaded Page's nomination.

David is BMI's second Kellett Awardee in recent years. Professor Michael Newton, who is joint with Statistics, is a Kellett Awardee named in the 2012-13 Academic Year.

The award is generously provided by the University of Wisconsin-Madison Office of the Vice Chancellor for Research and Graduate Education, with funding from the Wisconsin Alumni Research Foundation.

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