Thesis (Ph. D. in Medical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 143-153). / The field of medical image analysis continues to expand as magnetic resonance imaging (MRI) technology advances through increases in field strength and the development of new image acquisition and reconstruction methods. The advent of echo planar imaging (EPI) has allowed volumetric data sets to be obtained in a few seconds, making it possible to image dynamic physiological processes in the brain. In order to extract meaningful information from functional and diffusion data, clinicians and neuroscientists typically combine EPI data with high resolution structural images. Image registration is the process of determining the correct correspondence. Registration of EPI and structural images is difficult due to distortions in EPI data. These distortions are caused by magnetic field perturbations that arise from changes in magnetic susceptibility throughout the object of interest. Distortion is typically corrected by acquiring an additional scan called a fieldmap. A fieldmap provides a direct measure of the magnetic perturbations, allowing distortions to be easily computed and corrected. Fieldmaps, however, require additional scan time, may not be reliable in the presence of significant motion or respiration effects, and are often omitted from clinical protocols. In this thesis, we develop a novel method for correcting distortions in EPI data and registering the EPI to structural MRI. A synthetic fieldmap is computed from a tissue/air segmentation of a structural image using a perturbation method and subsequently used to unwarp the EPI data. Shim and other missing parameters are estimated by registration. We obtain results that are similar to those obtained using fieldmnaps, however, neither fieldmaps nor knowledge of shim coefficients is required. In addition, we describe a method for atlas-based segmentation of structural images for calculation of synthetic fieldmaps. CT data sets are used to construct a probabilistic atlas of the head and corresponding MRI is used to train a classifier that segments soft tissue, air, and bone. Synthetic fieldmap results agree well with acquired fieldmaps: 90% of voxel shifts show subvoxel disagreement with those computed from acquired fieldmaps. In addition, synthetic fieldmaps show statistically significant improvement following inclusion of the atlas. In the second part of this thesis, we focus on the inverse problem of reconstructing quantitative magnetic susceptibility maps from acquired fieldmaps. Iron deposits change the susceptibility of tissue, resulting in magnetic perturbations that are detectable with high resolution fieldmaps. Excessive iron deposition in specific regions of the brain is associated with neurodegenerative disorders such as Alzheimer's and Parkinson's disease. In addition, iron is known to accumulate at varying rates throughout the brain in normal aging. Developing a non-invasive method to calculate iron concentration may provide insight into the role of iron in the pathophysiology of neurodegenerative disease. Calculating susceptibility maps from measured fieldmaps is difficult, however, since iron-related field inhomogeneity may be obscured by larger field perturbations, or 'biasfields', arising from adjacent tissue/air boundaries. In addition, the inverse problem is ill-posed, and fieldmap measurements are only valid in limited anatomical regions. In this dissertation, we develop a novel atlas-based susceptibility mapping (ASM) technique that requires only a single fieldmap acquisition and successfully inverts a spatial formulation of the forward field model. We derive an inhomogeneous wave equation that relates the Laplacian of the observed field to the D'Alembertian of susceptibility, and eliminates confounding biasfields. The tissue/air atlas we constructed for susceptibility-based distortion correction is applied to resolve ambiquity in the forward model arising from the ill-posed inversion. We include fourier-based modeling of external susceptibility sources and the associated biasfield in a variational approach, allowing for simultaneous susceptibility estimation and biasfield elimination. Results show qualitative improvement over two methods commonly used to infer underlying susceptibility values and quantitative susceptibility estimates show stronger correlation with postmortem iron concentrations than competing methods. / by Clare Poynton. / Ph.D.in Medical Engineering

Thesis (Sc. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (p. 169-182). / The ability to form auditory objects is important in the natural environment where sounds arriving at our ears are a resultant of all spectro-temporal components that may have arisen from different auditory events. It has been shown that auditory spatial cues are effective for grouping acoustical energy across time or across frequency. However, little is known about the effect of spatial cues on scene analysis when more than one auditory object is being presented. In this thesis dissertation, a novel two-object paradigm was used to investigate how spatial cues influence the identification and the localization of object in the auditory foreground. Specifically, the effect of both spatial and non-spatial cues on auditory grouping and object identification was ascertained. Using an acoustic pointer and the same stimuli for the object identification task, the apparent spatial location of these objects was measured to test the hypothesis that only the spatial attributes of the components grouped to form an object influences the localization of the same object. A conceptual model was generated to highlight the role of spatial cues in object formation, and the dissociation between the auditory computation of "what" and "where" was further investigated. In current technology, object segregation presents a fundamental challenge for the hearing impaired, hearing aid design and speech recognition algorithms. It is hopeful that the findings in this dissertation will inspire new biologically-based algorithms for auditory scene analysis and in turn, influence designs in assistive hearing devices and other technological development that is dependent on multi-source segregation. / by Adrian Kuo Ching Lee. / Sc.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 57-59). / Generics in the pharmaceutical industry have been instrumental in reducing overall healthcare cost and allowing for greater dispersal of life saving drugs to the general population. The Hatch-Waxman Act of 1984 played a critical role in changing the landscape of the pharmaceutical industry and providing legislation for an abbreviated regulatory pathway for generic drugs. The conversation has shifted to the need to implement similar regulatory paths for generics of biologics. First generation biologic patents have or are geared to expire within the next five years, providing a great opportunity for generic companies in this space to enter. Biologic generics, termed biosimilars or follow-on biologics, are more difficult to evaluate due to the complex nature of the molecule and the variables involved in the development and manufacturing process. This research seeks to understand the current debate in the biosimilar conversation, and examine whether there is a clear regulatory path to market for biosimilars using epoetin as a case example across the three main markets; US, Europe and Japan. / byZeenat Patrawala. / S.M.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1997. / "August, 1997." / Includes bibliographical references. / by Nada Boustany. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 82-88). / This thesis asks one basic question: how do "vertical" disease- or intervention-focused global health programs impact the underlying health systems of the nations they serve? Vertical programs-health aid focused on a particular disease, such as HIV, or type of intervention, such as immunization-receive the lion's share of global health aid dollars, and yet we know uncomfortably little about their long-run impact on broader health systems. Many speculate that vertical aid undermines health worker effectiveness, distorts national policies, and disrupts the supply chain for drugs and medical products. Unfortunately, a lack of hard data makes quantitative analysis extremely difficult. Using the tools of system dynamics, this thesis consolidates the collective wisdom of previously published investigations and anecdotal observations to reveal the field's prevailing "mental model" of the dynamic in question. The result is a set of diagrams that describe the known impacts of vertical programs on health systems, and also reveal dynamic effects not yet explicitly identified in the literature. These effects fall into four sub-systems of impact: care delivery specialization and fragmentation, care delivery development and mediocritization, health policy development and mismatch, and market development and distortion. These models are then used to better understand the effects of recent contextual developments-the HIV/AIDS epidemic and the emergence of large Global Health Initiatives. / (cont.) Through expert interviews, this thesis identifies the most pressing system stresses in this contemporary context: the commitment to chronic care delivery which HIV/AIDS intervention creates, and the critical need for harmonization between donors which this commitment reveals. Using case examples from Kenya, these dynamics are shown to be active today, and to have instigated mitigation strategies by practitioners in the field. Finally, the systems identified above bring into focus key leverage points, including donor coordination, health worker augmentation, and engagement of local markets, which can "tip" the impact of vertical programs from harming health systems to strengthening them. In doing so, this thesis provides guidance to policymakers and program implementers who seek to use their resources to strengthen systems and eventually obviate health aid entirely. / by Brian J. Newkirk. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 91-98). / Large health cohort studies are among the most effective ways in studying the causes, treatments and outcomes of diseases by systematically collecting a wide range of data over long periods. The wealth of data in such studies may yield important results in addition to the already numerous findings, especially when subjected to newer analytical methods. Bayesian Networks (BN) provide a relatively new method of representing uncertain relationships among variables, using the tools of probability and graph theory, and have been widely used in analyzing dependencies and the interplay between variables. We used BN to perform an exploratory analysis on a rich collection of data from one large health cohort study, the Nurses' Health Study (NHS), with the focus on breast cancer. We explored the data from the NHS using BN to look for breast cancer risk factors, including a group of Single Nucleotide Polymorphisms (SNP). We found no association between the SNPs and breast cancer, but found a dependency between clomid and breast cancer. We evaluated clomid as a potential riskfactor after matching on age and number of children. Our results showed for clomid an increased risk of estrogen receptor positive breast cancer (odds ratio 1.52, 95% CI 1.11-2.09) and a decreased risk of estrogen receptor negative breast cancer (odds ratio 0.46, 95% CI 0.22-0.97). / (cont.) We developed breast cancer risk models using BN. We trained models on 75% of the data, and evaluated them on the remaining. Because of the clinical importance of predicting risks for Estrogen Receptor positive and Progesterone Receptor positive breast cancer, we focused on this specific type of breast cancer to predict two-year, four-year, and six-year risks. The concordance statistics of the prediction results on test sets are 0.70 (95% CI: 0.67-0.74), 0.68 (95% CI: 0.64-0.72), and 0.66 (95% CI: 0.62-0.69) for two, four, and six year models, respectively. We also evaluated the calibration performance of the models, and applied a filter to the output to improve the linear relationship between predicted and observed risks using Agglomerative Information Bottleneck clustering without sacrificing much discrimination performance. / by Delin Shen. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Vita. / Includes bibliographical references. / The development of high resolution, high speed imaging techniques allows the study of dynamical processes in biological systems. Optical fluorescence microscopy is an essential tool for investigations in many disciplines in biology and medicine with molecular specificity. The resolution of optical far-field microscopy has been limited by the wave nature of light. In this thesis, a microscopy technique, standing wave total internal reflection fluorescence (SW-TIRF), has been developed with resolution beyond the classical diffraction limit. The SW-TIRF approach modifies the point-spread function to effectively decrease the excitation wavelength by utilizing an evanescent standing wave, carrying high spatial frequency information near the interface between the specimen and a high refractive index substrate. Evanescent standing wave illumination is used to generate a sinusoidal, high-spatial frequency, fringe pattern on the specimen providing lateral resolution enhancement. Furthermore, the less than 100 nm penetration depth of the evanescent field from the substrate ensures a thin excitation region resulting in low background fluorescence. The first experimental realization of SW-TIRF in an objective-launched geometry demonstrates the potential for super-resolution imaging at high speed in wide-field microscopy. / (cont.) The super-resolution has been realized with the effective point-spread function providing better than a fifth of the emission wavelength or approximately 100 nm, which is better than twice that of conventional microscopy. In addition, imaging biological specimens with SW-TIRF demonstrated the performance revealing the fine actin cytoskeleton structures of fibroblasts. On the other hand, the surface plasmons induced by evanescent fields at a specific angle can generate an enhanced electric field which can effectively excite fluorophores near a metal coated surface. We observed a unique doughnut-shaped point-spread function of surface plasmon coupled emission and explained it with theoretical modeling using vector field theory. The combination of surface plasmon resonance fluorescence imaging and SW-TIRF resulted in a novel high-resolution microscopy, the standing wave surface plasmon resonance fluorescence (SW-SPRF) microscopy. These findings may allow super-resolution imaging with even higher sensitivity and signal-to-noise ratio at high imaging speed. / by Euiheon Chung. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (p. 65). / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Drug development in the United States is a lengthy and expensive endeavor. It is estimated that average development times range from eleven to fifteen years and exceed costs of one billion dollars. The development pathway includes basic scientific discovery, pre-clinical testing in animals, clinical development in humans, and an application process. The Food and Drug Administration is responsible for the oversight and approval of drugs going through this process. Numerous financial and economic studies have been conducted that show the benefits to accelerating the drug development process. In 1992, the United States Congress enacted the Prescription Drug User Fee Act I, which mandated faster response times from the FDA in return for user fee payments to the FDA by the drug developing companies. Data on approval times for new drugs indicate that this process was indeed shortened. In contrast, the average drug development process prior to the filing of an application has been increasing in cost and time. The first purpose of this research is to quantify the benefits of accelerated new drug application review time under the Prescription Drug User Fee Acts I and II. The second purpose of the research is to investigate what industry and the FDA can do together to reduce the development process time between the IND and NDA without compromising patient safety and welfare, specifically the Phase II, Phase III, and NDA components. The research indicates that PDUFA has improved approval times in a statistically significant way. Furthermore, the financial and social benefits as measured using net present value have far exceeded the PDUFA costs. Quantitative and qualitative surveys of fifty individuals in large pharmaceutical and biotech companies / (cont.) resulted in the identification of several significant opportunities and useful suggestions for reducing development times in Phase II, Phase III, and the NDA. Specifically, company interviewees indicated that they were willing to pay additional monies for increased interaction and communication with the FDA from Phase II through the NDA in hopes of reducing information asymmetry and increasing information transparency. Other recommendations included a mandatory audit and review of a sample of NDAs post approval to identify best practices, implementation of metrics and performance tracking during clinical phases, and implementation of consistent project management and communication standards across therapeutic divisions. / by Adrian Hedley Benjamin Gottschalk. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1998. / Includes bibliographical references (leaves 214-229). / by Stephen Allen Boppart. / Ph.D.

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 48-49). / Hepatocytes are widely used in the pharmaceutical and medical fields for drug metabolism studies, bioartificial liver devices, and repopulation of damaged livers as an alternative to transplantation. However, these cells are scarce and difficult to maintain in culture for prolonged periods of time. Banks of cryopreserved liver cells would significantly alleviate issues of hepatocyte availability, and efforts are being made to improve the viability and functionality of frozen hepatocytes. Previously, most work on improving post-thaw viability has hinged on limiting the physical damage of freezing by adding cryoprotective agents and optimizing cooling rates. Membrane-permeable cryoprotectants, such as dimethyl sulfoxide, though widely used, can be extremely toxic to the cell. More natural, non-membrane-permeable cryoprotectants, inspired by freeze-tolerant animals have also been used. A non-metabolizable glucose analog, 3-0-methyl- glucose (30MG), has shown promise with hepatocytes and was used in this study. Kinetics of the rGLUT2 cellular transporter used for 30MG uptake were quantified; Km and Vmax were determined to be 27.6 mM and 1.38 mM/s, respectively, by Lineweaver-Burk analysis and 70.0 mM and 1.82 mM/s, respectively, by Eadie-Hofstee analysis. This study also aimed to investigate the role of mitochondria in cell death induced by freezing. In particular, mitochondrial membrane potential (MMP) was investigated as a predictor of a cell's likelihood to avoid apoptosis from freeze-induced stress. Cells were sorted into high and low MMP subpopulations, frozen, thawed, and cultured for 24 hours. / (cont.) Cell cultures were analyzed for attachment yield, viability of attached cells and overall viability, which were 87%, 68% and 59%, respectively for the high MMP subpopulation, and 68%, 53% and 35%, respectively for the low MMP subpopulation. Morphological differences such as extent of membrane blebbing were observed as well, verifying that cells with a high MMP are more likely to survive the cryopreservation process. These results demonstrated that MMP is a determinant of both frozen hepatocyte adherence efficiency and viability; a high MMP yields a significant advantage in both. Our understanding of the role of MMP in freeze-thaw death and of the characteristics of the rGLUT2 transporter will lead to the development of more successful cryopreservation protocols. / by Margaux E. Daly. / M.Eng.