Thesis: Ph. D. in Health Sciences and Technology: Computer Science, Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Variations in atmospheric oxygen levels can be traced over evolutionary time and track closely with the development of multicellular life, speciation events, appearance of placental mammals and the creation of a cardio-respiratory system. As the final electron acceptor for aerobic ATP production, oxygen allows energy-intensive metabolic pathways to exist. Furthermore, oxygen is the most utilized substrate for known biochemical reactions, surpassing even ATP and NAD+. As a result, variations in oxygen levels have far-reaching consequences on human physiology and health. Mitochondrial disorders are the most common inborn errors of metabolism, affecting approximately 1 in 5000 live births. Patients can present in infancy or adulthood with symptoms affecting multiple organ systems including blindness, deafness, muscle weakness, developmental delay and severe neurological impairment. Unfortunately, there are currently no proven therapies for mitochondrial disorders. My thesis work has focused on combining systems biology, animal physiology and cellular metabolism approaches to develop new therapies for these disorders. More specifically, I have identified hypoxic breathing, equivalent to living at 4500m altitude, as protective in the setting of severe mitochondrial disease. First, I performed a genetic screen and found paradoxically, that hypoxic breathing and hypoxia responses are protective in mitochondrial disease. I then characterized the physiology and preclinical regimens of hypoxia therapy, laying the groundwork for translation to human patients. Fascinated by such a vital role for oxygen in human disease, I went on to define adaptive pathways in varying oxygen tensions. This work highlights the differential reliance on entire organelles at extreme oxygen levels. And finally, I studied the metabolic and proteomic consequences of defects in peroxisome metabolism and disease. / by Isha Himani Jain. / Ph. D. in Health Sciences and Technology: Computer Science

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (p. 215-227). / Instead of focusing on the cell, or the genotype, or on any single measurement modality, using integrative biology allows us to think holistically and horizontally. A disease like diabetes can lead to myocardial infarction, nephropathy, and neuropathy; to study diabetes in genomic medicine would require reasoning from a disease to all its various complications to the genome and back. I am studying the process of intersecting nearly-comprehensive data sets in molecular biology, across three representative modalities (microarrays, RNAi and quantitative trait loci) out of the more than 30 available today. This is difficult because the semantics and context of each experiment performed becomes more important, necessitating a detailed knowledge about the biological domain. I addressed this problem by using all public microarray data from NIH, unifying 50 million expression measurements with standard gene identifiers and representing the experimental context of each using the Unified Medical Language System, a vocabulary of over 1 million concepts. I created an automated system to join data sets related by experimental context. / (cont.) I evaluated this system by finding genes significantly involved in multiple experiments directly and indirectly related to diabetes and adipogenesis and found genes known to be involved in these diseases and processes. As a model first step into integrative biology, I then took known quantitative trait loci in the rat involved in glucose metabolism and build an expert system to explain possible biological mechanisms for these genetic data using the modeled genomic data. The system I have created can link diseases from the ICD-9 billing code level down to the genetic, genomic, and molecular level. In a sense, this is the first automated system built to study the new field of genomic medicine. / by Atul Janardhan Butte. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 135-141). / Bilateral cochlear implantation seeks to restore the advantages of binaural hearing to the profoundly deaf by giving them access to binaural cues normally important for accurate sound localization and speech reception in noise. This thesis characterizes binaural interactions in auditory neurons using a cat model of bilateral cochlear implants. Single neuron responses in the inferior colliculus (IC), the main nucleus of the auditory midbrain, were studied using electric stimulation of bilaterally implanted intracochlear electrode arrays. Neural tuning to interaural timing difference (ITD) was emphasized since it is an important binaural cue and is well represented in IC neural responses. Stimulation parameters were explored in an effort to find stimuli that might result in the best ITD sensitivity for clinical use. The majority of IC neurons were found to be sensitive to ITD with low-rate constant-amplitude pulse trains. Electric ITD tuning was often as sharp as that with acoustic stimulation in normal-hearing animals, but many neurons had dynamic ranges of ITD sensitivity limited to a few decibels. Consistent with behavioral results in bilaterally implanted humans, neural ITD discrimination thresholds degraded with increasing pulse rates above 100 pulses per second (pps). / (cont.) Since cochlear implants typically encode sounds by amplitude modulation (AM) of pulse-train carriers, ITD tuning of IC neurons was also studied using AM pulse trains. Many IC neurons were sensitive to ITD in both the amplitude envelope and temporal fine structure of the AM stimulus. Sensitivity to envelope ITD generally improved with increasing modulation frequency up to 160 Hz. However, the best sensitivity was to fine structure ITD of a moderate-rate (1000 pps) AM pulse train. These results show that bilateral electric stimulation can produce normal ITD tuning in IC neurons and suggest that the interaural timing of current pulses should be accurately controlled if one hopes to design a bilateral cochlear implant processing strategy that provides salient ITD cues. In additional experiments, we found that evoked potentials may be clinically useful for assigning frequency-channel mappings in bilateral implant recipients, such as pediatric patients, for which existing psychophysical methods of matching interaural electrodes are unavailable. / by Zachary M. Smith. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, February 2012. / "February, 2012." Cataloged from PDF version of thesis. / Includes bibliographical references (p. 185-209). / Articulation of multisyllabic speech requires a high degree of accuracy in controlling the spatial (positional) and the temporal parameters of articulatory movements. In stuttering, a disorder of speech fluency, failures to meet these control requirements occur frequently, leading to dysfluencies such as sound repetitions and prolongations. Currently, little is known about the sensorimotor mechanisms underlying the control of multisyllabic articulation and how they break down in stuttering. This dissertation is focused on the interaction between multisyllabic articulation and auditory feedback (AF), the perception of one's own speech sounds during speech production, which has been shown previously to play important roles in quasi-static articulations as well as in the mechanisms of stuttering. To investigate this topic empirically, we developed a digital signal processing platform for introducing flexible online perturbations of time-varying formants in speakers' AF during speech production. This platform was in a series of perturbation experiments, in which we aimed separately at elucidating the role of AF in controlling the spatial and temporal parameters of multisyllabic articulation. Under these perturbations of AF, normal subjects showed small but significant and specific online adjustments in the spatial and temporal parameters of articulation, which provided first evidence for a role of AF in the online fine-tuning of articulatory trajectories. To model and explain these findings, we designed and tested sqDIVA, a computational model for the sensory feedback-based control of speech movement timing. Test results indicated that this new model accurately accounted for the spatiotemporal compensation patterns observed in the perturbation experiments. In addition, we investigated empirically how the AF-based online speech motor control differed between people who stutter (PWS) and normal speakers. The PWS group showed compensatory responses significantly smaller in magnitude and slower in onset compared to the control subjects' responses. This under-compensation to AF perturbation was observed for both quasi-static vowels and multisyllabic speech, and for both the spatial and temporal control of articulation. This abnormal sensorimotor performance supports the hypothesis that stuttering involves deficits in the rapid internal transformations between the auditory and motor domains, with important implications for the neural basis of this disorder. / by Shanqing Cai. / Ph.D.

Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 111-116). / Ovarian cancer is the fifth leading cause of cancer-related deaths in women and the deadliest gynecologic cancer. The current standard treatment for advanced ovarian cancer includes a minimally invasive cytoreduction surgery, followed by intravenous (IV) or intraperitoneal (IP) chemotherapy with cisplatin and taxol. Clinical trials showed that the IP cisplatin treatment regimen was able to prolong overall survival by 16 months but only 42% of subjects completed all cycles of the IP therapy. The primary reason for the early termination of the IP treatment is catheter-related complications. The implantation of the catheter is also a complex procedure that can only be performed at premier centers by trained personnel. An alternative for IP administration that eliminates catheter-related complications and simplifies IP drug administration would therefore allow more patients to enjoy the benefits of IP therapy. A drug delivery device for use in a mouse model was developed as a tool to prove that maintaining a low constant cisplatin concentration in the peritoneal cavity and serum would improve the treatment outcome and reduce drug-related toxicity in ovarian cancer, compared to periodic IP bolus drug infusion. The device demonstrated highly linear and easily tunable in vitro release and exhibited excellent in vitro-in vivo correlation. Investigations of the device pharmacokinetics in vivo proved that the device was able to maintain a low and constant cisplatin concentration both locally in the peritoneal cavity and in the serum over up to six weeks. In vitro cytotoxicity of continuous cisplatin dosing with various human ovarian cancer cells lines was demonstrated. An in vivo xenograft SKOV-3 tumor model was established and optimized to reflect the distribution of ovarian cancer metastases in humans. The device achieved effective tumor growth retardation without systemic toxicity. An IP bolus injection scheme with a similar area-under-curve (AUC), however, caused severe bone marrow depletion. The results verified that the treatment efficacy correlates with the AUC but not the peak concentration, Cma. These promising preclinical results highlight the potential of this new therapeutic regimen to change the course of ovarian cancer care and warrant the need for designing a human device before proceeding to human trials. / by Hongye Ye. / Ph. D. in Medical Engineering and Medical Physics

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 12). / Telephone linked care (TLC) is a telehealth intervention that has been shown to be effective in a variety of clinical settings. TLC is an interactive computerized telephone system. The system 'speaks' to patients, asking them questions and understanding their responses. There is logic built into the calls, so that a patient's response to a question will dictate the next question that is asked. This serves to personalize the call for each patient, and makes the conversation more realistic. All of the patients' responses are stored in a database. This database provides much opportunity for analysis because a single phone call contains many responses. Visualization is an important way of gaining insight into data. Visualization can make data easier to understand and process. Different aspects of data can be encoded in a visualization. The TLC data lends itself to visualization. By viewing each of the questions that the system asks as nodes, and connecting the nodes by the chronological order in which these questions are asked, a tree structure will reveal the conversational paths that are taken in the calls. By combining data from multiple calls and encoding them in this tree structure, new insights can be gained into the TLC data. For example, the frequency with which questions are answered in a particular way can be encoded to reveal the most common pathways through the tree. This paper describes a visualization application of TLC data which will allow researchers to gain new insights into the TLC conversations and into medical interviews in general. / by Penelope H. Cuevas. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student submitted PDF version of thesis. / Includes bibliographical references (p. 127-132). / Clinical voice specialists make critical diagnostic, medical, therapeutic, and surgical decisions by coupling visual observations of vocal fold tissue motion with auditory-perceptual assessments of voice quality. The details of the relationship between vocal fold tissue motion and the voice produced are not fully understood, and there is recent evidence that the diagnostic significance of asymmetries during vocal fold vibration may be over-interpreted during clinical voice assessment. An automated system based on high-speed videoendoscopy recordings was developed to objectively quantify vocal fold vibratory asymmetry with initial validation from manual markings and visualperceptual judgments. Efficient estimation of these measures was possible due to recent technological advances in high-speed imaging of the larynx that enabled the capture and processing of high-resolution video (up to 10,000 images per second) of rapid vocal fold vibrations (100-1000 times per second). Synchronized recordings of the acoustic voice signal were made to explore physiological-acoustic relationships that were not possible using clinical stroboscopic imaging systems. In an initial study of asymmetric vibration in 14 patients treated for laryngeal cancer, perturbations in the voice signal were most associated with asymmetry that changed across vibratory cycles, while the overall level of asymmetry did not contribute to degradations in voice quality measures. / (cont.) Thus, since stroboscopic imaging is only able to capture vibratory asymmetry that occurs periodically, voice clinicians are not able to observe the time-varying nature of asymmetry that presumably affects acoustic perturbations to a higher degree. The impact of asymmetric vibration on spectral characteristics was explored in a computational voice production model and an expanded group of 47 human subjects. Surprisingly, in both model and subject data, measures of vocal fold vibratory asymmetry did not correlate with spectral tilt measures. In the subject data, left-right phase asymmetry and closing quotient exhibited a mild inverse correlation. This result conflicted with model simulations in which the glottal area waveform exhibited higher closing quotients (less abrupt glottal closure) with increasing levels of phase asymmetry. Results call for further studies into the applicability of traditional spectral tilt measures and the role of asymmetric vocal fold vibration in efficient voice production. / by Daryush Dinyar Mehta. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / 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. 191-200). / Electronic transmission of protected health information has become pervasive in research, clinical, and public health investigations, posing substantial risk to patient privacy. From clinical genetic screenings to publication of data in research studies, these activities have the potential to disclose identity, medical conditions, and hereditary data. To enable an era of personalized medicine, many research studies are attempting to correlate individual clinical outcomes with genomic data, leading to thousands of new investigations. Critical to the success of many of these studies is research participation by individuals who are willing to share their genotypic and clinical data with investigators, necessitating methods and policies that preserve privacy with such disclosures. We explore quantitative models that allow research participants, patients and investigators to fully understand these complex privacy risks when disclosing medical data. This modeling will improve the informed consent and risk assessment process, for both demographic and medical data, each with distinct domain-specific scenarios. We first discuss the disclosure risk for genomic data, investigating both the risk of re-identification for SNPs and mutations, as well as the disclosure impact on family members. Next, the deidentification and anonymization of geospatial datasets containing information about patient home addresses will be examined, using mathematical skewing algorithms as well as a linear programming approach. Finally, we consider the re-identification potential of geospatial data, commonly shared in both textual form and in printed maps in journals and public health practice. We also explore methods to quantify the anonymity afforded when using these anonymization techniques. / by Christopher A. Cassa. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 102-110). / Autocrine signaling plays essential roles in providing self-sustaining growth signals to cancer cells. Since the introduction of the autocrine hypothesis in 1980s, the contribution of autocrine signaling in cancer medicine has been limited to cancer tissues with adequately characterized mitogenic pathways. Its closed-loop nature and complex interplay with other environmental cues prevents the experimental study of unknown autocrine loops, requiring specific perturbing agents to inhibit the underlying ligand/receptor interactions. Recent studies reported the ability of drug-resistant cancer cells to acquire mitogenic signals from previously neglected autocrine loops, causing tumor recurrence. Methods that can evaluate autocrine-loop dependency in more diverse cancer tissues will help identify other means that autocrine signaling employs to maintain cancer growth. This thesis presents the use of cell-patterning methods as a tool for modulating intrinsically generated diffusive signaling cues. Such technology enables the investigation of autocrine loops without the need for specific therapeutics or prior knowledge of underlying ligand/receptor pairs. To achieve this goal, the first aim of this thesis is to determine characteristics of autocrine signaling that pertain to modulation of intercellular spacing, using existing investigation methods. In addition to demonstrating the limitation of conventional methods in examining unknown autocrine loops, we showed that changes of intercellular spacing in randomly plated culture cannot specifically modulate autocrine activity, due to the concurrent changes of other environmental cues. The second aim of this thesis is to establish engineering tools for 1) ensuring modification of only autocrine loops with the modulated cell arrangement and 2) providing prediction of autocrine activity changes with varying intercellular spacing. We illustrated cell-patteming approaches for introducing spatial regularity to standard cell culture. We then developed a stochastic model to predict changes of ligand/receptor binding with varying cell arrangement designs. We determined the spatial requirement for autocrine activity to transition from the isolated to the communicative mode. The model also helps determine cell-patterning designs that can potentially maintain uniform impacts of non-diffusive signaling cues while enabling specific modulation of autocrine signaling. In the last aim of this thesis, we evaluated the ability of regularly-shaped cell arrays to demonstrate the impact of autocrine signaling in supporting cancer growth. In comparison to randomly-plated culture, the cellpatterning platform exhibited growth change with altering intercellular spacing that better corresponds with the predicted and measured changes of autocrine ligand capture. With increasing global cell density, we also showed that regularly-shaped cell arrays acquire more uniform distribution of local cell density, while the randomly-plated cells exhibit distinct changes of local cell density. We present in this thesis the first method for the modulation of combined autocrine activity while ensuring minimal concurrent alteration of non-diffusive cues without the need of specific perturbing agents. / by Somponnat Sampattavanich. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 147-163). / Success in otologic practice is currently limited by the diagnostic tools and treatment options available to address an individual's specific presentation of hearing loss. This limitation results from insufficient characterization of the inner ear's biochemical environment as well as physical hurdles associated with accessing inner ear tissues. The encapsulation of the hearing organ within a bony shell and delicate nature of its tissues make standard tissue biopsy techniques impossible and leave many imaging methods impractical. This thesis sought to approach these clinical limitations in two ways: (1) performing novel transcriptional and translational characterizations of inner ear tissues and (2) development of a novel technique to access and communicate diagnostic information from within the inner ear. The first part of this thesis employs whole transcriptome shotgun sequencing to study murine inner ear transcriptional activity in young, healthy animals as well as changes associated with organ aging and noise-induced auditory neuropathy, an important mechanism of hearing impairment in humans. Knowledge of the inner ear's transcriptional behavior (Part I) is coupled with novel translational insights provided by high-throughput tandem mass-spectrometry (Part III) studies of human inner ear fluids obtained from healthy and pathologic populations. These studies illuminate homeostatic mechanisms employed by the highly specialized inner ear tissues, providing a critical knowledge-base for inner ear scientists and pharmacologists, and identify important expression-level changes which occur during the onset and progression of inner ear pathologies. While these high-throughput studies offer the powerful ability to gain a wealth of knowledge into which genes are active within the inner ear, functional assessment of the specific role these genes play must be assessed in a more focused manner. Phenotypic characterization of mice with specific genetic mutations (Part II) has been performed to provide critical insight into the specific role Fgf23 plays in development and maintenance of the auditory system. The second arm of this thesis seeks to provide clinical practicality to the above work by developing a method to safely access the inner ear environment to gather and communicate diagnostic information (Part IV). A guinea pig model was utilized to develop an approach to insert microelectrodes into the fluid spaces of the inner ear in order to harness and monitor the natural electrochemical gradient of the organ. The useful energy extracted from this "biological battery" was used to power a combined microchip/radio transmitter capable of performing voltage-sensing operations within endolymph and wirelessly relaying this information to an external receiver. This study was the first to utilize a mammalian electrochemical potential to power an electronic device. By performing this task while preserving the integrity of the hearing organ this work provides the first, critical proof-of-concept demonstration toward clinically-applicable sensing and therapeutic devices powered by the inner ear. Further refinement of this technique into a long-term, fully-implantable device will enable previously impossible longitudinal studies of organ behavior in awake, behaving subjects and the incorporation of sensing modalities into current inner ear prostheses to monitor biochemical changes and maximize patient benefits. / by Andrew Christopher Lysaght. / Ph. D.