Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from student-submitted PDF version of thesis. / Includes bibliographical references (p. 139-142). / In recent years, research in human speech communication suggested that the inventory of sound units that are observed in vowels across languages is strongly influenced by the acoustic properties of the human subglottal system. That is, there is a discrete set of possible vowel features that are constrained by the interaction of the acoustic/articulatory properties of the vowels and a small set of attributes that are observed in the subglottal region. This thesis tests the hypothesis that subglottal resonances govern vowel feature boundaries for three populations: adult speakers of English; adult speakers of Korean; and children learning English. First, we explored the relations among F1 of vowels, the first subglottal resonances (SubF1) and the feature [low] in English. For the diphthong [??], F1 peaks for vowels showed an acoustic irregularity near the speaker' s SubF1. For monophthongs, analysis of F1 frequency distributions shows a boundary between [+low] and [-low] vowels at the speakers' SubF1. Second, we studied the relations among F2 of Korean vowels, SubF2 and the feature [back], to test whether the relation between subglottal resonances and the feature boundary, demonstrated earlier for English, also can be applied to other languages. Results show that the F2 boundary between [back] and [front] vowels was placed near SubF2 in Korean, as in English. Third, we explored the development of vowel formants in relation to subglottal resonances for 10 children in the age range of 2;6-3;9 years using the database of Imbrie (2005). Results show that at the earlier ages, formant values deviated from the expected relations, but during the six month period in which the measurements were made, there was considerable movement toward the expected values. / (cont.)The transition to the expected relations appeared to occur by the age of 3 years for most of these children, in a developmental pattern that was inconsistent with an account in terms of simple anatomical increase. These three sets of observations provide evidence that subglottal resonances play a role in defining vowel feature boundaries, as predicted by Stevens' (1972) hypothesis that contrastive phonological features in human languages have arisen from quantal discontinuities in articulatory-acoustic space. / by Youngsook Jung. / Ph.D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2001. / Includes bibliographical references (p. 137-151). / Deep vein thrombosis (DVT) of the lower extremity and induced pulmonary embolism are common complications resulting from prolonged periods of bed-rest or immobilization of the limbs. One of the most effective methods of prophylaxis against DVT is external pneumatic compression (EPC). In spite of its wide acceptance as an effective means of prophylaxis, its mechanism remains poorly understood and optimal compression conditions have not been defined. Understanding the biological consequences of EPC is an important goal for optimizing the performance of compression device and providing guidance for clinical use. In the first part of this thesis, a computational model of the leg was developed to simulate hemodynamic conditions under EPC and the influence of different modes of compression were analyzed and compared. Then, a new in vitro cell culture system was developed that can be used to examine the effect of hemodynamic conditions during EPC on endothelial cell (EC) function. The biologic response was assessed through changes in cell morphology and the expression of various pro-thrombotic and anti-thrombotic factors related to EC. / (cont.) The results show that intermittent flow associated with EPC up-regulates EC fibrinolytic potential and vasomotor function. Using DNA microarray technology, the data of thrombo-regulatory factors indicates that EC gene expression shifts toward anti-thrombotic vs. pro-thrombotic under EPC. Finally, Nitric Oxide (NO), an important regulator of vasomotor and platelet functions was studied in detail under various cycles of EPC. The results show that NO production and eNOS mRNA respond differentially to modes of EPC. Further exploration using the system can potentially reveal the optimum combination of forces to better regulate thromboresistant effects desired for DVT prophylaxis. / by Guohao Dai. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references (leaves 38-40). / A recent analysis by the Tufts Center for the Study of Drug Development estimates that the cost of developing a single new chemical entity (NCE) into a successful therapeutic agent is $802 million. This figure is largely dependent on the expense of investigating NCEs that ultimately fail to be approved for use: between 70 - 90% of NCEs do not achieve New Drug Application (NDA) approval, and many of these failures are identified during the later, more costly phases of drug development. The exponential growth in the number of putative NCEs as a result of combinatorial chemistry and high-throughput screening has only confounded this problem by significantly increasing the number of early-phase NCEs under consideration for further costly development in human clinical trials. It is widely agreed upon that there are 3 major categories of reasons for drug failure: safety (toxicity), efficacy, and economics. This thesis is concerned with developing a Bayesian domain-knowledge probabilistic model (called Pharminator) to address the first two of these categories, with a goal of predicting clinical success of an NCE. Pharmacoeconomic modeling is a vastly different domain compared to Pharminator's clinical trial domain, and is beyond the scope of this thesis. While several clinical predictive models have been described in the literature over the past 10 years, the ongoing costly failure rate in drug development warrants developing more reliable predictors of NCE clinical success. The number of NDA approvals in 2002 fell to a 5-year low of 18, compared to 30, 35, 27, and 24 in 1998, 1999, 2000, and 2001 respectively, despite rapidly increasing numbers of NCEs as a result of high-throughput screening and combinatorial chemistry. / (cont.) Therefore, previous decision models have had no apparent impact on this problem. The Pharminator model combines knowledge of drug development logistics, existing data on NCE attrition rates, and Bayesian decision theory in a manner that may improve upon the performance of previously described models. The product of this model is an application to be used by drug development teams at the Phase I/Phase IIa time point for a given NCE that has passed the FDA Investigational New Drug (IND) screening process. The users are prompted to answer several key questions about the NCE. and conditional probability The tables are to be used in the model, as well as the observed data upon which prediction will be made. The output is a numeric and graphical (distribution plot) report of the prior and posterior probability distributions for clinical success, safety and efficacy. The application is demonstrated on one fictional agent and one real agent designed to demonstrate key behaviors of the model. Retrospective and prospective testing and validation will continue beyond the completion of this thesis in order to optimize the performance of this model. / by Asher Daniel Schachter. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 137-154). / Neovascularization is an essential process to repair ischemic tissues following myocardial infarction, stroke, diabetic complications, or transplant procedures. Blood vessels are generated by distinct vasculogenic and angiogenic processes. Although multiple proangiogenic factors have been identified, limited success has been achieved translating these as clinical therapeutics. Furthermore, recent studies have shown that vasculogenesis contributes to adult neovascularization in multiple settings. Harnessing the vasculogenic potential of embryonic stem cells is an emerging concept to generate neovasculature. The differentiation of embryonic stem cells into endothelium has been well documented, however most studies focus on genetic or chemokine regulation. Limited information exists which implicates the role of the extracellular microenvironment in stem cell differentiation. Heparan sulfate glycosaminoglycans (HSGAG) are a crucial part of the dynamic extracellular matrix and have been shown to regulate multiple signaling cascades, including vasculogenic specific growth factors VEGF and FGF. The goal of this thesis is to elucidate the role of HSGAG in vasculogenesis. An embryonic stem cell embryoid body model was used to establish the necessity of sulfated HSGAG for endothelial differentiation. We identified that the chemical composition of HSGAG sulfation patterns change with differentiation. Perturbation of HSGAG structure by chemical, enzymatic, or genetic modification effectively inhibited vasculogenesis. Genetic silencing of HSGAG modifying enzyme, N-deacetylase/N-sulfotransferase-1, translated to inhibition of HSGAG sulfation and resulted in impaired blood vessel development in zebrafish embryos. Interestingly, vessel formation in both embryonic stem cell and zebrafish models was restored by the addition of exogenous HSGAG, opening the door for engineering glyco-based microenvironments for controlling vascular development. To explore novel mechanisms of vasculogenesis modulated by HSGAG perturbation, we performed a global transcriptome analysis of N-deacetylase/N-sulfotransferase-1 mutant zebrafish embryos. Several novel pathways were identified that regulate vascular differentiation, including Foxo3A and Insulin-Like Growth Factor (IGF) pathways. We explored the role of IGFs in vasculogenesis specifically and determined for the first time that IGF1 and IGF2 promote mesoderm and endothelial differentiation, mediated through HIFl[alpha] stabilization, in embryonic stem cells. In summary, we've identified several mechanisms by which HSGAG regulate neovascularization, laying the groundwork for incorporating HSGAG in strategies for ischemic tissue regeneration. / by Stephanie Marie Piecewicz. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references. / Simultaneous recording of electroencephalogram (EEG) and functional magnetic resonance imaging (tMRI) is an important emerging tool in functional neuroimaging with the potential to reveal new mechanisms for brain function by combining the high spatial resolution of fMRI with the high temporal resolution of EEG. Applications for this technique include studies of sleep, epilepsy, and anesthesia, as well as basic sensory, perceptual, and cognitive processes. Unlike methods that combine these modalities from separate recordings, simultaneous recordings can reveal temporal correlations between EEG and fMRI. Simultaneous recordings also eliminate environmental confounds inherent with separate recordings. MRI systems produce electromagnetic interference that can corrupt sensitive electrophysiological recordings, making simultaneous recordings challenging. Gradient switching and RF pulses can saturate EEG amplifiers, and cardiac pulsation within the static magnetic field produces large artifact signals ("ballistocardiogram") that confound EEG analysis. In this Ph.D. thesis, we develop an EEG acquisition system compatible with fMRI at 3 and 7 Tesla, a method for eliminating the ballistocardiogram artifact using adaptive filtering, and use these methods to study the 40-Hz auditory steady-state response (ASSR). The adaptive filtering method outperforms existing standard methods by up to 600%. The ASSR is a sub-microvolt level auditory evoked potential related to sleep, consciousness, and anesthesia. / (cont.) Simultaneous recordings of ASSR and fMRI reveal that spontaneous fluctuations in the amplitude of the ASSR are represented throughout the auditory system, from cortex to brainstem, suggesting that brainstem structures play an important role in generating the 40-Hz ASSR and that integration of sensory information across multiple hierarchical scales, including the earliest portions of the central nervous system, may constitute an important component of awareness or arousal. / by Patrick L. Purdon. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 62-68). / Fifteen years ago lin-4 was reported to be the first endogenous small non-coding, but interfering RNA structure involved in developmental timing in C. elegans. First thought not, or only rarely, to occur in mammals, microRNAs are now among the major players in up-to-date genomic research. The mature molecules are ~22 nucleotides in length and, by targeting predominantly the 3' UTR of mRNAs, lead to translational repression or degradation of the target message, hence controlling important cellular mechanisms, including division, differentiation and death. This key role makes them excellent targets for cancer research. In fact they have been shown to have a major impact on cancer development in many cases. However, miRNAs are not a homogeneous class and can be sub classified into intragenic and intergenic, depending on their genomic position. Whereas intergenic miRNAs are expected to be independent transcriptional units, intragenic miRNAs are commonly believed to be regulated through their host gene. Despite of the growing knowledge on how miRNAs integrate into cellular regulatory networks, our current knowledge about the specific role of intragenic miRNAs is rather limited. In this work we integrated current miRNA knowledge bases, ranging from miRNA sequence and genomic localization information to target prediction, with biochemical pathway information and publicly available expression data to investigate functional properties of intragenic miRNAs and their relationship to their host genes. To the best of our knowledge, we are the first to show in a large-scale analysis that intragenic miRNAs seem to act as negative feedback regulators on multiple levels. We furthermore investigated the impact of this model on the potential role of intronic miRNAs in cancer pathogenesis. / by Ludwig Christian Giuseppe Hinske. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 59-61). / Innovation within the medical device industry had led to tremendous advances in the provision of care for patients worldwide. Continued progress in the treatment of disease will require effective processes for managing and analyzing innovation within this industry. Popular models of innovation exist for many industries outside of the medical realm; however, an extensive literature search uncovered a limited body of work related to innovation within the medical device industry. Specifically, literature that examines the application of the principles of disruptive innovation to the medical device industry is limited in scope and in quantity. It is theorized that the medical device industry may have unique characteristics for disruptive innovation due to the unique economic and regulatory structures that exist within this industry. This thesis applies the principles of disruptive innovation that were popularized by Clayton Christenson's seminal work, "The Innovator's Dilemma", to the medical device industry. These characteristics are subsequently delineated and evaluated through examination of the prosthetic cardiac valve industry. This industry serves as an effective case study due to the long history of innovation and the emergence of new disruptive technology within this specialty. The categorization of a "disruptive" innovation was made when a given technology altered the value proposition for treating a disease, relative to incumbent technology. This case study was evaluated along metrics of performance characteristics, the perception of leading customers, the ability to prospectively analyze markets, and the profitability of disruptive innovation for the incumbent firm. Conclusions were reached based on an examination of relevant literature and primary research conducted with thought leaders in this area. This research supports the conclusion that the cardiac valve industry has experienced unique characteristics in the development and commercialization of disruptive innovations. Specifically, incentives appear to exist within this industry that support development and commercialization of disruptive innovations by industry incumbents. Furthermore, the importance of understanding what value proposition is being disrupted is paramount in effectively understanding the incentives of manufacturers to innovate. When a technology is developed that is disruptive to a procedure, then the manufacturer tends to behave similar to a "newentrant" within the Christenson framework. This appears to also be true when the innovation is disruptive to that manufacturer's legacy products. Additional research is warranted in extrapolating this finding to the broader medical device industry. / by David B. Berlin. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, September 2003. / "August 2003." / Includes bibliographical references (p. 54-57). / For Parkinson's patients to function at their best, their medications need to be optimally adjusted to the diurnal variation of symptoms. For this to occur, it is important for the managing clinician to have an accurate picture of how the patient's bradykinesia/hypokinesia and dyskinesia fluctuate throughout the normal daily activities. This thesis proposes the use of wearable accelerometers coupled with machine learning and statistical techniques in order to classify the movement states of Parkinson's patients and to provide a timeline of how the patients fluctuate throughout the day. A pilot study was performed using 2 patients with the goal of assessing the ability to classify dyskinesia and bradykinesia/hypokinesia based on accelerometric data. The patients were observed and videotaped. Clinical observations of bradykinesia/hypokinesia and dyskinesia were noted every minute. Neural networks were able to classify better than classification trees with an average c-index (equivalent to the area under the ROC curve) of 0.905 for bradykinesia/hypokinesia and 0.926 for dyskinesia. A separate group of 5 patients were observed with the additional goal of building models that can classify the movement of a patient without requiring clinically annotated training data for the same patient. An enhanced protocol was used in the final study. Dichotomized linear regression was found to classify well with an average c-index of 0.8219 for body bradykinesia/hypokinesia and 0.8799 using as the gold-standard the patient's diary. Dyskinesia was classified at a c-index of 0.7522. Neural networks did not perform as well, possibly because of restrictions placed on adjusting parameters. The two most clinically important problems: predicting / (cont.) when the patient feels he/she is "off' or when he/she has "troublesome dyskinesia" were discriminated with c-indices of 0.96 and 1.0 respectively. The good result of the models despite the small number of patients is promising. Further studies with larger number of patients are therefore justified. / by David A. Klapper. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 69-73). / Personalized medicine is the science and practice of customizing medical screening and treatment plans for an individual based on his or her genomic profile. Breast cancer is one of the first disease areas to serve as an example of this approach, where most patients have experienced its benefits through the use of genetic tests that provide decision support for health care workers regarding the likely effectiveness of specific drugs and, more broadly, the urgency of particular treatment options (for example, chemoprevention versus prophylactic surgery). Little is known about the diffusion of such personalized approaches to medical practice, particularly the factors shaping the adoption of genetic tests. While numerous medical diffusion studies have been published over the past few decades, most were univariate analyses and did not consider the unique aspects of genetic testing versus drugs. Moreover, they mainly focused on the characteristics and behaviors of physicians, patients, product manufacturers, and social networks, and did not explore the role of potentially important third parties like professional medical societies and patient groups (e.g. disease foundations and patient advocacy organizations). The aim of this thesis was to analyze the relationship between seven attributes of four breast cancer genetic tests and clinical adoption to show that standard diffusion frameworks can be enhanced through previously unstudied dimensions when evaluating personalized medicine-related innovations. / (cont.) We identified four variables that correlated with clinical adoption: 1) regulatory status, 2) inclusion in practice guidelines by professional societies, 3) explicit endorsement by patient groups, and 4) implicit endorsement by patient groups. Our findings indicate that a key overlooked element in the current literature (and potentially overlooked by the firms creating these tests) is the role of patient groups in the diffusion of novel genetic tests, in addition to endorsement from medical professional societies. These findings may add value to strategic decisions made by company executives, investors, payers, health care providers, and patients as they are presented with novel products and development opportunities in the era of personalized medicine. / by Julie Keunhee Yoo. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 83-85). / The pipeline productivity challenge facing large, publicly traded pharmaceutical companies, collectively referred to as "Big Pharma," is well known. The unprecedented success Big Pharma achieved over the past few decades in commercializing blockbuster products means that it is now faced with near-term patent expirations on such products, representing billions of dollars in lost sales and profits. In order to maintain its economic momentum, Big Pharma is increasingly relying on the universe of smaller, early stage biotechnology and pharmaceutical companies as a source of new products. Early stage companies may offer Big Pharma something beyond simply more product bets. Several recent consulting studies have shown that economic returns to Big Pharma of products sourced externally are greater than those developed internally, which raises the question: What, if anything, are early stage companies doing differently from Big Pharma in their product development programs? The goal of this thesis is to evaluate product development programs ("projects") and compare qualitatively and quantitatively the decisions for projects at key decision points between early stage pharmaceutical and biotechnology companies and Big Pharma. Given that much of the critical discovery and R&D work on pharmaceutical products happens both before and during a product's entry into human clinical trials, this thesis focuses on those areas of the development continuum where R&D plays a central role. The key decision points are therefore: lead candidate selection/optimization, moving a project from pre-clinical trials into Phase I human clinical trials, and moving a project from Phase I to Phase II clinical trials in humans. / (cont.) The thesis tests the hypothesis that small, early stage, publicly traded U.S. & Canadian biotech and pharma firms (Small Pharma) focused on 1-2 therapeutic areas who high levels of homogeneity in their decision making process, number of decision inputs, prioritization processes, and metrics for all three key decision points in the product development process irrespective of whether a product originates inside or outside the company. In comparison, Big Pharma companies will show heterogeneity in these variables for their projects. I have obtained data from primary interviews of industry executives within Big Pharma and Small Pharma firms. The therapeutic areas selected for the early stage company data set are: (1) cancer and autoimmune disease, (2) cardiovascular disease, and (3) infectious disease. The rationale for these therapeutic areas is that there is significant drug development activity taking place in these fields, and there are significant unmet medical needs within them. Additionally, both Big Pharma and Small Pharma companies are developing products in these fields. I compare these data sets statistically using Fisher's exact test and Yates' chi-square test. / by Daniel S. Rippy. / S.M.