Julian Little, MA, PhD
Professor and Chair
Dr. Julian Little, Professor and Chair (August 2006) of the Department of Epidemiology and Community Medicine, is the Canada Research Chair in Human Genome Epidemiology (March 2005).
Program of Research
Since taking up the Canada Research Chair in April 2005, the aim of Dr Little’s research program in Human Genome Epidemiology has been the application and further development of epidemiologic methods in a multidisciplinary context to the translation of gene discoveries into actions to improve health. The program has four specific areas:
- Methodological work in pursuit of the “road map” for human genome epidemiology that Dr. Little developed with collaborators;
- Gene characterization;
- Development and evaluation of genomic-related health applications, including stratification on the basis of familial risk; and
- Congenital anomalies.
1. Methodological work in pursuit of the “road map” for human genome epidemiology
The “road map” for understanding the role of genetic variation in human health and how to use evolving knowledge to improve health and prevent disease was developed in response to concerns about non-replication of findings and methodological issues in genetic association studies. The road map includes:
- Developing a “network of networks” linking teams of investigators in order to develop a system for controlling publication bias and selective reporting. This initiative grew out of two HuGENet workshops in Cambridge, UK, in which Dr Little was an organizer. HuGENet (Human Genome Epidemiology Network) was created to help translate genetic research findings into opportunities for preventive medicine and public health;
- Increasing the transparency of reporting of genetic association studies. Dr. Little led initiatives to obtain funding from multiple sources and organized international workshops in Ottawa and also as part of Population Project in Genomics (P3G) meetings that led to the STREGA (STrengthening the REporting of Genetic Association studies) statement, published in 2009. 15 journals have explicitly supported STREGA either by publishing the statement, a commentary on it or referring to it in their instructions to authors. In addition, the statement is included on the Equator, Consort and US National Library of Medicine websites. Dr. Little’s group also carried out a CIHR-funded project to assess the reporting of genetic association studies and investigate the relationship between aspects of the methods reported to have been used to investigate genetic associations and the direction and magnitude of the results obtained (Al_Jasir, completed MSc thesis; paper in advanced stage of preparation); this work will also serve as a baseline to assess the effect of the STREGA guideline. This evaluation of reporting was recently extended to include genome-wide association studies (Yurkiewich, MSc project in progress);
- Developing harmonization of methods across studies. This is being taken forward through the Public Population Project in Genomics (P3G), funded by Genome Canada, including a series of workshops and meetings, one of which was specifically on calibration (for which additional funding obtained from CIHR, Generation Scotland and the PHOEBE project, funded by the European Commission). Following the calibration workshop, a systematic review of calibration studies was initiated (protocol under journal review; Landry, MSc project in development). Since 2006, Dr. Little has co-chaired with Muin Khoury (Director, National Office of Public Health Genomics, CDC) the International Working Group on Epidemiology and Biostatistics. In addition to the STREGA Statement, this activity has led to publications on realistic sample size requirements for detection of gene-environment joint effects, further solidifying the need for international harmonization, on methods for harmonization and a systematic review of theoretical and empirical evidence on the validity of the case-only study design (funded by Cancer Care Ontario; Dennis, MSc thesis 2010 and paper under review);
- Developing methods for synthesis and meta-analysis of genetic association data. Dr Little has been involved in the Human Genome Epidemiology (HuGE) Network since 1998, particularly developing the concept of HuGE reviews. Dr. Little co-organized a workshop that led to the development of a handbook for these reviews incorporating methodological principles developed by the Cochrane group, and papers disseminating this. This appears to have had a positive impact; and
- Developing “field synopses” in order to capture and appraise the state of evolving evidence across entire fields of study. Dr. Little chaired the planning group for this workshop that led to publications on the concept and an initial book chapter about its application to colorectal cancer. A full field synopsis was submitted to Nature Genetics in April 2011.
2. Gene characterization
This objective has been pursued focusing on the substantive areas of colorectal neoplasia (Sharp PhD thesis 2005; Hutchings MSc thesis 2007; Tait MSc thesis 2009; Demarsh, MSc thesis 2011), orofacial clefts (Johnson MSc thesis 2008) and the fetal anticonvulsant syndrome. With regard to genetic factors mediating response to therapy, we developed a concept paper on the epidemiological approach to pharmacogenomics and the work on case-only studies. To enable gene characterization in the longer term, Dr. Little has been collaborating in the development of the Ontario Health Study, on which he served as a member of the interim leadership team, and on the harmonization of large-scale cohorts and biobanks (P3G project). Building on the work done for the TOMBOLA trial, he has been working to enable inclusion of samples in the International Cervical Cancer Consortium GWA study of cervical intraepithelial neoplasia.
3. Genomic-related health applications
Initial work with collaborators in CDC that suggested that multiple common variants of modest effect could, when bundled together, account for a substantial proportion of the population attributable fraction for common diseases. As a result, further simulation analysis of the potential value of such a test, and empirical evaluation applied to colorectal cancer has been ongoing (Demarsh MSc thesis 2011).
Systematic reviews on the clinical validity and clinical utility of ascertaining family history of common cancers in primary care, and of chronic diseases more generally, funded by AHRQ have been published (Hasanaj MSc thesis in progress). Data from international collaborative studies of brain tumours in children and adults (Thomson MSc thesis 2006; paper in preparation) have been analysed. Family history is also being included in the assessment of predictive value of multiple genetic variants for colorectal cancer and in the CIHR Emerging Team in Genomics in Screening.
Dr. Little has continued work on the Trial Of Management of Borderline and Other Low-grade Abnormalities (TOMBOLA), funded by the UK Medical Research Council and the National Health Service in England and Scotland. This was a pragmatic randomized controlled trial of cytological surveillance compared with initial colposcopy, and within the colposcopy arm, a further randomized comparison of immediate large loop excision of the transformation zone (if abnormal) and biopsy and selective recall for treatment. Testing for human papillomavirus infections (HPV) associated with high risk for cervical cancer was done prior to randomization so that both randomizations could be stratified on HPV status, and the trial was powered to detect interactions between trial arm and HPV status; a total of 4500 women were randomized. Dr. Little led the preparation of the grant application, obtained funding, and was PI until his move to Canada. Since then, he has continued to be involved in the Trial Executive and Management Groups, and is now chairing a group concerned with nested genetic studies. This has given opportunities for advanced training (Cotton PhD thesis, 2008: Cochran MSc thesis, 2007; Gray PhD thesis, 2007) and a series of publications has resulted. The results of this trial are expected to have an impact on policy making within population-based cervical screening programs. Dr. Little has started to develop work on integration of approaches to prevent cervical cancer in Canada (Navaneelan and Rambout MSc projects in progress).
Dr. Little’s involvement in the Ontario Advisory Committee on Newborn and Childhood Screening has stimulated collaborative survey and qualitative work on issues relating to the expansion of newborn screening in the province, and the issue of disclosure of sickle cell carrier status in particular (grants from Ontario Ministry of Health and Long Term Care and CIHR).
Following his participation in the workshop leading to the establishment of the Genome-based Research and Population Health International Network (GRaPH Int) in 2005, Dr. Little served on the Executive Committee which was co-ordinated by the Office of Biotechnology, Genomics and Public Health of the Public Health Agency of Canada from 2006-2010. In addition, the group has published overviews of public health genomics, including newborn screening, in Canada and the Gulf States.
4. Congenital anomalies
There has been concern about the adequacy of surveillance in Canada, and Dr. Little has been serving on the Canadian Congenital Anomaly Surveillance Network Advisory Group since 2005, chairing a Working Group 2006-9, and now serves on the Committee to Implement Enhanced Surveillance and contributed to the organization of the 4th-8th annual scientific meetings. He has also been a member of the Ontario Congenital Anomalies Committee since December 2010, and is a member of a team that recently received a grant from PHAC to develop congenital anomalies surveillance in the province. Other work includes gene characterization and largely focuses on orofacial clefts.
Dr. Julian Little
Department of Epidemiology & Community Medicine
University of Ottawa
451 Smyth Road, RGN 3231
Ottawa, Ontario K1H 8M5
Phone: 613-562-5800 ext. 8159
Administrative Assistant: Valery L'Heureux