Thesis (Ph. D.)--Harvard University--MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (p. 229-233). / This thesis addresses the design and evaluation of algorithms to improve speech reception for cochlear-implant (CI) users in adverse listening environments. We develop and assess performance metrics for use in the algorithm design process; such metrics make algorithm evaluation efficient, consistent, and subject independent. One promising performance metric is the Speech Transmission Index (STI), which is well correlated with speech reception by normal-hearing listeners for additive noise and reverberation. We expect the STI will effectively predict speech reception by CI users since typical CI sound-processing strategies, like the STI, rely on the envelope signals in frequency bands spanning the speech spectrum. However, STI-based metrics have proven unsatisfactory for assessing the effects of nonlinear operations on the intelligibility of processed speech. In this work we consider modifications to the STI that account for nonlinear operations commonly found in CI sound-processing and noise reduction algorithms. We consider a number of existing speech-based STI metrics and propose novel metrics applicable to nonlinear operations. A preliminary evaluation results in the selection of three candidate metrics for extensive evaluation. In four central experiments, we consider the effects of acoustic degradation, N-of-M processing, spectral subtraction, and binaural noise reduction on the intelligibility of CI-processed speech. We assess the ability of the candidate metrics to predict speech reception scores. / (cont.) Subjects include CI users as well as normal-hearing subjects listening to a noise-vocoder simulation of CI sound-processing. Our results show that: 1) both spectral subtraction and binaural noise reduction improve the intelligibility of CI-processed speech and 2) of the candidate metrics, one method (the normalized correlation metric) consistently predicts the major trends in speech reception scores for all four experiments. / by Raymond Lee Goldsworthy. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (leaves 66-67). / In order to automate data extraction from electronic medical documents, it is important to identify the correct context of the extracted information. Context in medical documents is provided by the layout of documents, which are partitioned into sections by virtue of a medical culture instilled through common practice and the training of physicians. Unfortunately, formatting and labeling is inconsistently adhered to in practice and human experts are usually required to identify sections in medical documents. A series of experiments tested the hypothesis that section identification independent of the label on sections could be achieved by using a neural network to elucidate relationships between features of sections (like size, position from start of the document) and the content characteristic of certain sections (subject-specific strings). Results showed that certain sections can be reliably identified using two different methods, and described the costs involved. The stratification of documents by document type (such as History and Physical Examination Documents or Discharge Summaries), patient diagnoses and department influenced the accuracy of identification. Future improvements suggested by the results in order to fully outline the approach were described. / by Reejis Stephen. / S.M.

Thesis (Ph. D. in Electrical Engineering and Bioinformatics)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 102-103). / In the past decade, thousands of human genomes have been catalogued, either by whole-genome sequencing or by targeted genotyping. The variability between human genomes encodes invaluable information about human traits and genetic diseases, as well as human migration patterns and population interactions. A key challenge is to understand and characterize the evolution of the variability between human genomes. In this thesis, I focus on studying human evolution through the use of microsatellites, which are simple repetitive sections of DNA of typically 1-6bp motifs (e.g. CACACACACA) that are highly polymorphic and highly mutable. The first aim is to establish that microsatellites are useful as reliable molecular clocks, such that its evolution highly correlates to time, especially when applied to the time range appropriate for human history. Using existing models of microsatellites, we examine microsatellite data from populations around the world to demonstrate that microsatellites are accurate molecular clocks for coalescent times of at least two million years. These results raise the prospect of using microsatellite data sets to determine parameters of population history. In order to calibrate genetic distances into time, the mutation rate must be known. This leads to the second aim, which is to directly measure the microsatellite mutation rate from largescale pedigree genetics data and provide a precision that is unprecedented. To do so, we use data from over 95,000 individuals in Icelandic pedigrees, genotyped in over 3000 microsatellite loci. Using trio and extended-family based approaches, we discover 2058 denovo mutations. In addition, we also attempt to capture many features that are covariates with the mutation rate, such as parental gender and age. The third aim takes our empirical observations of the microsatellite mutation process to build a new model of microsatellite evolution. This model improves upon the standard random walk model with features we have captured from aim 2. We use a Bayesian coalescent approach to provide a model that estimates the sequence mutation rate, European genetic divergence times, and human-chimpanzee speciation time. / by James Xin Sun. / Ph.D.in Electrical Engineering and Bioinformatics

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1996. / Includes bibliographical references. / This thesis examines the problem of resource allocation in Africa to combat the HIV/AIDS epidemic. It focuses on the use of one specific technology, the anti-HIV antibody test. After describing the characteristics of the epidemic, the special problems that accompany the allocation of health resources in Africa are explored. A short description of the biological and technical aspects of HIV testing is followed by three case studies which examine different uses of the technology. (1) A model of the use of HIV testing to screen blood donors is demonstrated in several hypothetical situations to evaluate under which circumstances HIV screening is cost-effective and which is the most cost-effective of a number of testing systems. (2) Use of the HIV test is considered from a cost-effectiveness perspective for the purpose of helping to confirm the diagnosis of HIV-related disease. Possible benefits of testing (including more rapid initiation of appropriate treatment, avoidance of the cost and iatrogenic complications of inappropriate treatment, and more efficient rationing of health care resources) are compared to possible costs (including monetary costs, emotional costs, and costs associated with false test results). A detailed protocol is presented of a prospective study to evaluate the appropriate use of the HIV test in the inpatient hospital setting. (3) Serologic surveys, including procurement of samples and testing for HIV, comprise the bulk of any program to monitor and characterize the epidemiology of the HIV/AIDS epidemic. / (cont.) The descriptive data thus gathered can then be used to more effectively target interventions to prevent further HIV spread and alleviate the impact of HIV/AIDS. Two models are presented which can be used to optimize the cost-efficiency of serologic surveys by improving the selection of sample size and testing method. The conclusions draw upon the findings of the three case studies. They place the fight against AIDS in its social and economic context in Africa; outline the general rules that govern the use of HIV testing technology; and underscore the need for cost-effectiveness assessments to improve the efficiency of resource allocation by national AIDS programs. / by Stefano Michele Bertozzi. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 46-47). / There are various kinds of clinical documents used in a hospital or clinic setting. With the emergence of Electronic Medical Records, efforts are being made to computerize these documents in a structured fashion in order to enable decision support. With structured data entry, because each fact about the patient is stored discretely and can be retrieved separately, information can be organized and presented in different ways, depending on the needs of the user. A typical structured clinical document contains a range of findings recorded by a physician, nurse or other care. These findings can be thought of as discrete pieces of information, called observations. These observations can be grouped together to form observation sets that can be placed under relevant headers within the document. When building information systems that support structured clinical documentation, these observations and sets are created and stored in catalogs. My thesis addresses the issue of building an ontology model for clinical documentation that supports the creation and management of an observations catalog, observation sets catalog and a clinical document catalog. The ontology can be used as an organizational tool for efficient maintenance of these catalogs. By tagging observations and observation sets with relevant attributes, it is possible to generate intelligent displays of data that are more flexible and dynamic. / by Joyce George. / S.M.

Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 179-189). / Cochlear implants are devices that aim to restore a measure of hearing to the deaf by converting acoustic signals to electric stimuli delivered to electrodes implanted in the inner ear. Theoretically, the phased array stimulation strategy described by van den Honert and Kelsall (2007) provides much better control over the neural excitation patters elicited by electric stimulation by taking advantage of potential field superposition in the implanted cochlea, to construct stimuli for optimally selective excitation of auditory nerve fibers. If the phased array strategy can be implemented using a commonly-implanted commercial cochlear implant system, the strategy could be effectively evaluated in a relatively large sample of patients to determine whether it provides better speech reception than currently available systems. This thesis investigates whether the phased array strategy can be implemented using the Advanced Bionics Clarion CH or HiRes90k cochlear implant. It is shown that for realistic cochlear implant electrode impedance magnitudes, the Advanced Bionics cochlear implant current sources will deliver monopolar current suitable for the necessary measurement of transimpedance with less than 7% error. Transimpedance matrix estimates were obtained in 11 ears in 10 cochlear implant subjects. Measurements reveal that in some test subjects, low impedance current paths exist between implanted electrodes that may cause current leakage through unintended electrodes. Researchers and clinicians should consider using this transimpedance matrix estimation technique to screen for patients or research subjects who could benefit from compensatory changes to their speech processors. The results of this thesis suggest that the phased array strategy can be implemented successfully when the limitations of the internal power supply documented in this document are taken into account. It is recommended that the transimpedance matrix in a given test subject be measured on the day of any psychophysical testing because of the potential impact of variability in transimpedance over time. / by Matthew V. Crema. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (p. 46-49). / The pars tensa of the tympanic membrane is composed of three layers: an epidermal layer, a fibrous layer, and a mucosal layer. Recent studies (Kuijpers et al, 1999; Henson and Henson, 2000; Henson et al, 2005) suggest that the fibrous layer in several mammalian species contains contractile fibers, which are located primarily within the thickened border of the pars tensa known as the annulus fibrosis. These contractile fibers resemble smooth muscle fibers. Yang and Henson (2002) studied the physiological effects of pharmacological modulators on the pars tensa of the annulus fibrosis by measuring the sound-induced cochlear response. Their results suggest a dose-dependent change in cochlear response after application of sodium orthovanadate and norepinephrine. Application of saline induced no change in cochlear response. Based on their data, Yang and Henson proposed that the pharmacological agents altered the function of the smooth muscle fibers of the annulus fibrosis to produce a mechanical change in the tympanic membrane. In this study two measurements, cochlear response and Laser Doppler Vibrometry, were used to assess the sound-induced velocity of the tympanic membrane of the gerbil before and after application of saline and varying concentrations of three smooth muscle antagonists (sodium orthovanadate, norepinephrine, and carbachol) to the pars tensa. It was demonstrated that applications of saline and varying concentrations of sodium orthovanadate were associated with both increases and decreases in the magnitude of the cochlear response in two out of three ears tested. There was no evidence of a dose-dependent change in the cochlear response. / (cont.) Applications of saline and varying concentrations of sodium orthovanadate, norepinephrine, and carbachol were associated with increases and decreases in the magnitude of the Laser Doppler Vibrometry response in eight of fourteen ears tested. Evidence of a dose-dependent change in Laser Doppler Vibrometry results was obtained in one ear. The results of this study suggest that application of any substance to the tympanic membrane may or may not be associated with an increase or decrease in the cochlear response or Laser Doppler Vibrometry response, and thus, the source of mechanical changes observed at the tympanic membrane is not necessarily the smooth muscle fibers of the annulus fibrosis. / by Amanda J. Graves. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 131-139). / The practice of brachytherapy and brachytherapy dosimetry was investigated with emphasis on evaluations of dose distributions and shielding considerations for both photon- and neutron-emitting radionuclides. Monte Carlo simulation methods were employed to calculate dose distributions for virtual and commercial brachytherapy sources. Radionuclides studied were 103Pd, 1251, 131Cs, 137Cs, 169b, 192Ir, and 252Cf. 252Cf sources also emit neutrons from spontaneous fission. The brachytherapy dosimetry protocol recommended by the American Association of Physicists in Medicine was followed and evaluated for conditions of partial scatter (non-infinite media) and material inhomogeneities, both commonly encountered in brachytherapy treatment. Furthermore, energy-dependent characteristics of dosimetry parameters were evaluated and reference calculations performed for virtual photon and neutron sources. These findings were applied to three clinical brachytherapy cases: eye plaques using 103Pd, 125I, and 131Cs; high-dose rate 252Cf treatment; and, 2 Cf plaques for superficial lesions. For eye plaques, material heterogeneities were significant for each radionuclide with dose reduction at 5 mm of 18%, 11%, and 10% for P03pd, 125I, and 131Cs, respectively. For a proposed highdose rate 252Cf source (5mm length), relative brachytherapy dosimetry parameters were found to be similar to those obtained for a low-dose rate Applicator Tube-type source (15 mm length). Considering 252Cf plaque brachytherapy when partial scatter conditions were accounted for, central axis equivalent dose rate decreased by 11 ± 1% and 7 ± 2% for depths of 4 to 50 mm, respectively. / (cont.) The ratio of neutron dose to total physical dose was 70 ± 1% and 57 ± 2% for depths of 4 and 50 mm, respectively, while the fractional dose-equivalent due to neutrons was 93 + 1% and 89 ± 2% at these depths, respectively. Finally, shielding requirements for a clinical high-dose rate 252Cf source were explored for common shielding materials and a linear accelerator vault. Lead, polyethylene, and borated polyethylene were evaluated for neutron, primary photon, and secondary photon attenuation. Half-value layers of 0.70, 0.15, and 0.13 m were obtained for lead, polyethylene, and borated polyethylene, respectively. A linear accelerator vault was found to adequately shield up to a 5 mg 252Cf source for regular clinical use. / by Christopher S. Melhus. / Ph.D.

Thesis (S.M. in Health Sciences and Technology)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 60-61). / It has been estimated that 100 million plus individuals could perish if a virulent influenza pandemic were to occur. In wake of the 2009-10 H1N1 pandemic and in an era of economic austerity, however, industry lacks clear incentives to invest in vaccines for other high-risk strains. The cyclic nature of pandemics also means we can expect another influenza pandemic within the next 20 years. In this environment, design of incentive mechanisms for funding development of vaccines against strains with known pandemic potential, but for whom vaccine technology is currently lacking, would be welcomed. This research explores which novel incentive mechanisms could induce investment in and development of processes for production of vaccines for these high risk strains. Interviews with vaccine developers and funding agencies and analysis of the pipeline of influenza vaccines in development were conducted. This thesis finds that there is a dearth of vaccines against influenza strains of known pandemic potential, such as H2, H7 and H9; that current pandemic preparedness efforts are not focused on these strains; that funding for pandemic preparedness efforts in H2, H7 and H9 would help incentivize development of vaccines against these strains; and that support for seasonal influenza, regulatory changes, alignment of public and private sector goals, and increased vaccine acceptance are also required to incentivize the development of vaccines against strains of known pandemic potential such as H2, H7 and H9. Furthermore, this thesis recommends that policy makers increase funding for pandemic preparedness so that programs may be initiated or expanded to include additional high risk influenza strains; that US and EU regulatory regimes for pandemic influenza vaccines be harmonized; and that governments promote public awareness of the importance of influenza vaccination. / by Julia Kay Preis. / S.M.in Health Sciences and Technology

Thesis: S.M. in the Concentration of Mechanical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 28-31). / There is a critical health care need to generate large numbers of beta cells for transplantation. In Type 1 Diabetes (T1D), insulin-producing beta cells in the islets of Langerhans within the pancreas, which support glucose homeostasis, are destroyed in an autoimmune attack. The ensuing loss of glycemic control leads to serious complications, requiring life-long insulin injections and close monitoring, while shortening lifespan by 11-13 years. In the face of a three percent annual increase in T1D incidence, there is a grave lack of transplantable material, and very few patients are able to receive an islet transplant each year. Recent advances in stem cell differentiation have enabled the production of large quantities of insulin-producing beta-like cells in vitro, bringing hope to the field. However, the efficiency and yield of such production methods remains unacceptably low, with high batch-to-batch variability, and the function of these cells is unstable. Moreover, the ability to probe the conditions that affect differentiation outcomes is limited by the scale, cost, and complexity of existing culture systems. The present work focuses on the Disque Platform, a biomimetic screening platform for the investigation of islet cell differentiation. The Disque Platform allows for the formation of differentiating 3D micro-tissues within an automation-friendly design, and is capable of systematically manipulating the developing stem cell niche in order to identify chemical and physical cues that enhance beta cell production. Significantly, the Disque Platform consistently differentiates beta-like cells from pancreatic progenitor cells, with similar efficacy to existing high-volume production methods. Furthermore, it achieves superior differentiation outcomes compared to the 2D culture systems tested, and is able to respond to interventions when conventional systems cannot produce a clear signal or readout. Together, these data support the ability of the Disque Platform to investigate specific interventions to enhance beta-cell differentiation. It is hoped that the Disque Platform can serve as a springboard for beta cell and islet study within the diabetes community, and that these advances can contribute towards a cure for Type 1 Diabetes. / by Peter Anthony Jones. / S.M. in the Concentration of Mechanical Engineering