Current Research Interest/ProgramBreast Tissue Composition and Cancer Risk: Dr. Shepherd is investigating the measurement of breast tissue density as a surrogate for breast cancer. Other than age, breast density has been shown to be one of the strongest indicators of breast cancer risk. Women who have greater than 50% of total breast area that is mammographically dense are at 3 to 5 fold greater risk of breast cancer than women with less than 25% mammographically dense breasts. For these and other reasons, breast density could be used as a marker to predict breast cancer risk and possibly risk of disease recurrence or change in breast cancer risk. Current methods for quantifying breast density are not sensitive enough for drug trials or for monitoring treatment in individual women. These methods include categorical scoring methods and percent area ratios of the mammographically dense breast area to the total projected breast area.
Dr. Shepherd is extending this technique to directly measure breast tissue compositional density either from a mammogram using Single X-ray Absorptiometry (SXA) techniques, from Dual Energy X-Ray Absorptiometry (DXA) as an add-on exposure to full field digital mammography, from DXA on clinical bone densitometers, or from dedicated and custom built breast bioimpedance devices. All of these methods he has pioneered. Although he has many collaborations, he is the pioneer of these methods of breast densitometry and is internationally recognized as a independent leader in this field. He has the following collaborations within Radiology: Jessica Leung is our primary breast imaging specialist on a number of collaborations that involve her scoring of mammograms for semiquantitative breast density; Rebecca Smith-Bindman and John Kurhanewicz are collaborators on Dr. Shepherd’s Project on his P01 Program Grant Project. Dr. Smith-Bindman is also the gold standard for all of Dr. Shepherd’s mammographic density projects; Dr. Kurhanewicz is working with Dr. Shepherd to choline metabolites in different percent fat breast samples using High Resolution Magic Angle Spectroscopy; Yin Lu and Dr. Shepherd are co-investigators on an R01 to study cost effective models of diagnosis using Dr. Shepherd’s breast density measures in a large (+30,000 women); Catherine Klifa and Dr. Shepherd are working to verify new models of breast density against a MR gold standard; Dr. Malkov (Radiology) and Dr. Shepherd are investigating new automated breast density techniques and have a working version to analyze 45,000 mammograms annually at the CPMC cohort trial.
He has the following active projects and collaborations outside of Radiology: Drs. Steven Cummings (Epidemiology) and Karla Kerlikowske (Medicine) are epidemiologists working with Dr. Shepherd to utilize his densitometry techniques with clinical populations including women treated with raloxifen to prevent breast cancer (Cummings), the relationship between breast cancer risk factors bone density and breast density (Kerlikowske), and a prospective measure of breast density and serum markers in a large cohort of women receiving mammography at California Pacific Medical Center, CMPC (Cummings, Margolin); Drs. Thea Tlsty (Pathology) and Kerlikowske are investigating with Dr. Shepherd the biological basis of breast density (P01) by coupling histology and local breast density measures in several thousand samples from several hundred whole breast specimens; Dr. Shepherd is working with Dr. Jeffery Tice (Medicine) to explore the relationship of soy diets to breast density; Dr. Elad Ziv (Medicine) is working with Dr. Shepherd on relating breast density to genetic markers such as BRCA mutations. In addition, Dr. Shepherd has established a mammographic reading service within Radiology to be used by other investigators in the UC system to quantify mammographic density, breast volumetric density, and a novel measure parenchyma complexity. He co-chaired the 1st and 2nd Mammographic Density Workshop in the spring 2002 and 2004 and is preparing for the 3rd in 2007. The above work has generated numerous publications, grants, and oral meeting presentations to date.
Quantifying Bone Disease in Adolescents and special populations:Dr. Shepherd is an investigator with Dr. Emily von Scheven (Pediatric Rheumatology) to determine how to describe and monitor bone disease and body composition in children. This work is manifest in a cohort study of 375 children, 125 Lupus patients and 250 controls, using seven different x-ray absorptiometry modalities (hip, AP lumbar spine, lateral spine, QCT of the spine, forearm, quantitative ultrasound of the heel, radius, metacarpal and whole body). Dr. Shepherd's focus in this research is to remove gender, ethnicity, and age as confounders when interpreting bone quality measurements. Dr. Shepherd is an investigator with Dr. Vincente Gilsanz (Radiology, Los Angeles) to compare projectional spine bone density with quantitative computed tomography measures. Dr. Shepherd is a co-investigator with Drs. Mina Matsuda-Abedini (Pediatric Nephrology) and Anthony Portales (Pediatric Nephrology) regarding quantifying bone loss in children with renal failure. Dr. Shepherd is also an investigator in a multi-center trial to determine if alendronate is an effective treatment for children with low bone density. In addition, Dr. Shepherd has developed a method for subtracting DXA images from each other to visualize bone loss as a gradient map. Dr. Sven Prevrhal is a co-investigator with Dr. Shepherd to use this technique in an R01 proposal to sensitively indicate the early onset of osteolysis around total hip arthroplasty. 400 patients undergoing total hip arthroplasty will be monitored for 5 years and the DXA technique compared with a CT gold standard. Quality Assurance and Quality Control Methods
Dr. Shepherd is an independent and internationally recognized expert in Quality Assurance and Quality Control methods for quantitative measures such as bone density. He has developed phantoms for monitoring the accuracy and precision of boty bone densitometry systems as well as mammography devices. He is currently writing a book with Dr. Lu in Radiology on the Statistical Methods for Quality Control and Quality Assurance in Medical Diagnosis. Dr. Shepherd is the chair of the International Standards Committee on Bone Measurements and recently performed a meta analysis that lead to the first competency standards for radiation technologist using DXA systems. He is also collaborating with ISCD, NIST, ICRU, and Hologic, Inc. to develop a new phantom for whole body DXA quality assurance.
