Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (leaves 29-30). / Some have argued that the genetic differences between continentally defined groups are relatively small and unlikely to have biomedical significance. In this study, the extent of variation between continentally defined groups was evaluated. Small numbers of randomly selected single nucleotide polymorphisms from the International HapMap Project were used to train classifiers for prediction of ancestral continent of origin. Predictive accuracy was then tested on independent data sets. A high degree of genetic similarity implies that groups will be difficult to distinguish, especially when only a limited amount of genetic information is used. It is shown that the genetic differences between continentally defined groups are sufficiently large that one can accurately predict ancestral continent of origin using only a minute, randomly selected fraction of the genetic variation present in the human genome. Genotype data from only 50 random single nucleotide polymorphisms can be used to predict ancestral continent of origin in the primary test data set with an average accuracy of 95%. / (cont.) Single nucleotide polymorphisms were also characterized as being in introns, coding exons, regulatory regions and regions coding for untranslated mRNA and classifiers constructed using only single nucleotide polymorphisms from a specific category. Predictive accuracy was similar across all of the classifiers created in this manner. Single nucleotide polymorphisms useful for prediction of ancestral continent of origin are common and distributed relatively evenly throughout the genome. These findings demonstrate the extent of variation between continentally defined groups and argue strongly against the contention that genetic differences between groups are too small to have biomedical significance. / by Dominic J. Allocco. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000. / Includes bibliographical references (p. 133-137). / This research characterizes the respiratory system dynamics at the initiation and termination of utterances and determines correlations of physiological measures with acoustic cues for these prosodic boundaries. The analysis includes boundaries within a breath as well as boundaries that are aligned with the initiation and termination of exhalation. Simultaneous recordings of the acoustic signal, airflow, esophageal pressure and lung volume were collected during read isolated utterances and short paragraphs. These measures were used to derive estimates of recoil forces of the chest wall, net muscular forces, and the area of the airway constriction. Data are presented from four subjects (two men, two women), all native speakers of American English. Perceptual ratings for initial and final prominent syllables and the locations of pauses within the utterance were also collected. For speech boundaries th.i.t are aligned with breath boundaries, utterance initiation occurs during a rapid transition in muscular effort. Sound begins as soon as conditions permit and these conditions consistently occur during net inspiratory muscular force. Alveolar pressure reaches an initial peak (PpI) that is, in most cases, correlated to the relaxation characteristic of the chest wall. The timing of Pp1 generally coincides with a prominent syllable if that syllable is the first or second syllable in the utterance and precedes later prominences. Pressure at phonation onset is, on average, near 0.3PpI for utterances initiated with a voiced sonorant and is near 0. 8Pp1 for utterances initiated with a voiceless fricative. Phonation termination results from an approximately 3-fold increase in glottal area and a J-3 cm H20 fall in pressure. Irregular fundamental frequency (FO) at the end of voicing, in many cases, does not fit the classical definition of glottalization. Instead, voicing terminates with increasing glottal area, and FO becomes irregular during the increase. In some cases, regular FO resumes as glottal area continues to increase. Distinct respiratory gestures are made at pauses within a breath. The pressure is reduced by 2-3 cm H20, on average, during a period of relatively little volume change. The findings in this research show that the role of the respiratory system in speech production goes beyond a more traditional view of this role as one of simply providing a relatively constant driving pressure during speech. / by Janet Slifka. / Ph.D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000. / Includes bibliographical references (leaves 167-175). / by Christopher Joseph Long. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 80-84). / Many early-stage biotech companies face a significant funding gap when trying to develop a new drug from preclinical development to a proof of concept clinical trial. This funding gap is sometimes referred to as the "valley of death", a reflection of the vast number of companies that are unable to raise the needed capital to progress into the clinic. The suggestion behind the "valley of death" phrase is that companies that should be able to attract investment do not get funded, because (1) the technical risks inherent in taking a new drug through clinical trials are high, (2) a significant amount of capital is needed to finance clinical development, and (3) the time horizon of investment is on the order of 6-8 years. Ultimately, the valley of death reflects the perceived imbalance of risk and reward for an investment at this stage as well as the resulting difficulty for a biotech company in raising capital during this time. For companies focused on a neglected disease, this risk/reward profile is even more skewed, with significantly greater market risks and fewer exit opportunities for an investor. As a result, the "valley of death" phenomenon for a global health company developing a therapeutic for a neglected disease is even more pronounced As a result, private sector funding for translational research of neglected disease therapeutics has beeri severely lacking. In an effort to spur more private sector investment into the development of neglected disease therapeutics, several market design mechanisms have been developed including Advanced Market Commitments (AMCs) and Priority Review Vouchers (PRVs). These market design mechanisms are new and unproven. / (cont.) To date venture capital has not yet flowed in a meaningful way into startup companies focusing on neglected diseases. This is partially attributable to uncertainties surrounding the credibility and value of the incentives, but it also raises the question of whether these incentives will be sufficient to attract venture investment to a small biotech company focused on neglected diseases. The objective of this thesis is to explore the potential impact of these market design mechanisms on the financial prospects of early stage, pre-revenue biotech companies focused on neglected diseases, including an evaluation of whether the incentives will be sufficient to attract venture investment to the company. To accomplish this, a simulation model was created to compare the relative impacts of these incentive schemes on a small biotech company focused exclusively on a neglected disease therapeutic. The simulation data presented herein reflect the inherent tensions between the social benefit of a neglected disease therapeutic and the need for investors to pursue a financial return commensurate with the risk of the investment. I conclude that, while market design mechanisms like PRVs and AMCs are an intriguing first step, a dual market strategy is likely still necessary for a neglected disease company to attract private investment. / by Brian L. K. Miller. / S.M.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2001. / Includes bibliographical references. / This thesis presents a novel optical technique, light scattering spectroscopy (LSS), developed for quantitative characterization of tissue morphology as well as in vivo detection and diagnosis of the diseases associated with alteration of normal tissue structure such as precancerous and early cancerous transformations in various epithelia. LSS employs a wavelength dependent component of light scattered by epithelial cells to obtain information about subcellular structures, such as cell nuclei. Since nuclear atypia is one of the hallmarks of precancerous and cancerous changes in most human tissues, the technique has the potential to provide a broadly applicable means of detecting epithelial precancerous lesions and noninvasive cancers in various organs, which can be optically accessed either directly or by means of optical fibers. We have developed several types of LSS instrumentation including 1) endoscopically compatible LSS-based fiber-optic system; / (cont.) 2) LSS-based imaging instrumentation, which allows mapping quantitative parameters characterizing nuclear properties over wide, several cm2, areas of epithelial lining; and 3) scattering angle sensitive LSS instrumentation (a/LSS), which enables to study the internal structure of cells and their organelles, i.e. nuclei, on a submicron scale. Multipatient clinical studies conducted to test the diagnostic potential of LSS in five organs (esophagus, colon, bladder, cervix and oral cavity) have shown the generality and efficacy of the technique and indicated that LSS may become an important tool for early cancer detection as well as better biological understanding of the disease. / by Vadim Backman. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 55-57). / Recently, hospitals, regulatory agencies, and insurers have renewed their focus on improving patient care and safety. Outcomes based measures are being utilized and hospitals are being asked to report on whether patients are being treated according to a standard of care or a best practice guideline. As peri-operative physicians, anesthesiologists are able to evaluate and, to a great degree, affect the pre-operative, intra-operative, and post-operative course of a patient. However, several barriers exist. Although best practice guidelines exist, current models to risk stratify patients need improvement. Individual anesthesiologists currently have no uniform way to measure patient outcomes, either in an institutional or provider specific manner, and many treat patients based on anecdotal experience rather than on evidence based medicine. We addressed these issues through development of an electronic feedback system. The demonstration system targeted the problem of postoperative nausea and vomiting (PONV) in the ambulatory surgery patient population. Because performance of existing PONV risk prediction models was poor and could not be used for educational purposes, we created a new PONV risk prediction model and compared it against existing models. The new, improved risk prediction model was incorporated into an electronic system that gathered patient outcomes data related to best care practice and then fed back the information to care providers. After implementation of the electronic feedback system, we evaluated its efficacy in improving compliance with best care practices. / by Pankaj Sarin. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Vita. / Includes bibliographical references (leaves 72-76). / Prolonged exposure to microgravity in space flight missions (days) impairs the mechanisms responsible for defense of cardiac output (CO) and arterial blood pressure (Pa) against orthostatic stress during re-entry and in the post-flight period. To date, available countermeasures have not been able to eliminate the observed orthostatic hypotension. The mechanisms responsible for the observed orthostatic intolerance are not yet completely understood. Pa is maintained by control pathways, which influence either total peripheral resistance (Ra) or CO. Central control of Ra is achieved by a complex closed-loop negative feedback system composed of the arterial and the cardiopulmonary baroreflexes. The aims of the doctoral research presented in this thesis were: 1) design and employ a novel conscious animal model for the examination of arterial and cardiopulmonary baroreceptors in the dynamic closed-loop short-term control of Ra. 2) develop and apply a system identification method for the analysis of fluctuations in Pa, right atrial pressure (Pra), and Ra to quantitatively characterize the physiologic mechanisms responsible for the couplings between these variables. For this purpose, eight conscious sheep were used, where both types of baroreceptors were simultaneously exposed to random independent beat pressure variations over a small range around their operating points, while Ra was measured. Subsequently, system identification was applied to determine the quantitative dynamic contributions of Pa and Pra to short-term closed-loop regulation of Ra. To validate the dynamic properties of the transfer function estimates from the developed system identification method, step response estimates from Pa to Ra and from Pra to Ra were compared to directly measured step response observations. / by A. Nikolai Aljuri. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 66-73). / The United States is the world leader in development and manufacture of medical devices. Even with this leadership position, there is evidence that the US is often not the first country to have new medical technology approved for patient use. In many cases, the European Union is the first geographic region to approve a new medical technology for sale, with US approval coming later. This delay in approval of new devices between the EU and US is referred to as the "device lag." However, the extent or history of this lag over time and for different device types has not been examined. This thesis evaluated if a device approval lag has developed between US and EU at any time over the past 20 years and whether a device lag continues to exist today. US and EU regulatory approval data for 135 medical devices in three innovative medical device segments were collected and analyzed to evaluate the extent and history of the approval lag between the European Union and the United States. The collected approval data revealed a consistent approval lag between the US and EU in each of the three medical device segments explored in this study. Throughout the entire 20+ years of study, the United States had an average approval lag to the European Union in each of the three device segments, and an average lag for all devices of 21 months or almost 2 years (Ho: p. = 0, p = 8.2E-12). Furthermore, the device lag in these three segments has grown in recent years. These data are striking because they show, perhaps for the first time, that an approval lag has existed for medical devices between the US and EU for the past 20 years - since the beginning of the pan-European device regulatory system in the mid-1990s. The device lag is a useful metric for comparing the attractiveness of two markets for medical technology and may signal important changes in the medical technology industry. Furthermore, the existence of a persistent device approval lag in the United States may have significant implications for patients and their caregivers. / by Todd V. Dhavale. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (p. 142-146). / This study focuses on the acoustic patterns of stop consonants and adjacent vowels as they develop in young children (ages 2;6-3;3) over a six month period. Speech is generated using a series of articulatory, laryngeal, and respiratory gestures that children must learn to reproduce. As a child's speech develops, the gestures become more precise and coordinated, and the resulting acoustic patterns are refined. To explore their development, over forty different acoustic measurements were made on each of 1049 recorded utterances from ten children, including durational, amplitude, spectral, formant, and harmonic measurements. These acoustic data are interpreted in terms of the supraglottal, laryngeal, and respiratory actions that give rise to them. Data show that some details of the child's gestures are still far from achieving the adult pattern. Children have acquired appropriate positioning of their primary articulator for producing a stop consonant, but are still learning to adjust the tongue body during the consonant production. At constriction release, children have a high incidence of multiple bursts and a short burst duration, interpreted as a reflection of increased articulator compliance, smaller articulator size, and high subglottal pressure. Children are also still acquiring correct adjustment of vocal fold stiffness and glottal spreading as well as intraoral pressure, as evidenced by long voice onset times and highly variable fundamental frequencies. Additionally, amplitude changes over the course of the utterance and high amplitude variability reveal that children have not yet gained full control over subglottal pressure. / (cont.) Overall, results indicate that children are less consistent than adults in controlling and coordinating various gestures and with finding the ideal respiration and vocal tract postures, including the stiffness of their articulators. Certain aspects of child speech are found to become more similar to adult values over the six month period of the study. / by Annika Karin Karlsson Imbrie. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (p. 223-237). / The ear represents a remarkable achievement in sensory physiology. It is very fast (timescales on the order of 1-100 kHz), has a large bandwidth (-10 octaves in the human), highly sensitive (threshold is ultimately determined by thermal noise), operates over an enormous dynamic range (factor of a trillion in terms of energy input), capable of sharp stimulus selectivity (e.g. frequency and intensity discrimination) and exhibits robust nonlinear behavior. As a sensor designed to detect acoustic sound pressure, surprisingly, the ear also emits sound as well. These otoacoustic emissions (OAEs) have been developed extensively for clinical applications (healthy ears emits while impaired ones do not), though their full potential has yet to be realized. Much of the effort gone into understanding OAEs has been developed within the context of mammals, where specific anatomical and physiological features (e.g. traveling waves and somatic motility) are thought to play an integral role in generation. This thesis approaches OAEs comparatively, systematically characterizing emissions in humans and an array of non-mammals (chickens, geckos and frogs) who lack these mammalian features and exhibit a diverse range of morphologies. / (cont.) First, our results show that for a fixed set of stimulus conditions (employing moderate intensities), emissions are relatively largest in the gecko and frog (the two species with the fewest number of sensory cells) and smallest in the human and chicken for frequencies below -2 kHz. At higher frequencies (3-5 kHz), emissions descend toward the noise floor for the non-mammals but remain relatively constant in human. Second, OAE phase behavior indicates that emissions are generated by multiple mechanisms in the human and chicken (and possibly gecko in certain stimulus conditions), but not the frog. OAEs in all species exhibit significant delays (-1 ms or longer), those being largest in humans. Tuning can explain these delays in all species except the frog, where some additional source of delay is present. Lastly, non-monotonic growth (relative to stimulus intensity) was found in all species, suggesting the presence of multiple level-dependent sources. We interpret the observed similarities and differences in emission properties across species within the context of anatomical/physiological comparisons. / by Christopher Bergevin. / Ph.D.