Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 35-36). / In normal-hearing ears, sound waves are amplified within the cochlea and a small fraction of the sound energy travels backward out into the ear canal, producing sounds known as "otoacoustic emissions" (OAE) that can be measured with a sensitive microphone. One class of OAE, called "stimulus-frequency-otoacoustic-emissions" (SFOAEs), has been hypothesized to be produced by a process known as "coherent reflection filtering" (CRF). The CRF theory provides a prediction between the SFOAE group delay and the group delays of tone responses on the basilar membrane within the cochlea. Using single and multiple-tone stimuli, we collected data from the firing patterns of single auditory-nerve-fibers (ANFs) from which basilar-membrane tone-response group delays can be calculated for both high and low best-frequency (BF) positions along the basilar membrane. These calculated basilar-membrane group delays were compared to published SFOAE group delays. Our results suggest that group delays calculated from the tip, the lower-frequency tail, or the above-BF region of ANF tuning curves do not match the CRF theory prediction. In obtaining the data to the test the CRF theory, we used two methods for obtaining ANF group delays at frequencies above BF: a previously published method and a simpler new method based on the same principle. / (cont.) Surprisingly, the two methods produced different results. Control measurements suggest that the previously published method does not do what it was expected to do. / by Holden Cheng. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 72). / Alzheimer's disease (AD) is a field with huge unmet need and only a few symptomatic treatments with limited efficacy have been made available to patients. With the testing of disease-modifying drugs in recent years, the length of AD clinical trials has tripled and the enrollment has gone up drastically. These investigational disease-modifying drugs address new targets including the amyloid beta and tau protein aggregation pathways in the brain. They have opened up a whole research field on biomarkers specific to these pathways. These biomarkers have however never been used to select a subpopulation that would enroll in clinical trials. This thesis defines a framework for assessing any AD biomarker's quality as a selection tool for enrolling a subpopulation into an AD clinical trial. Carefully selecting the patient population with appropriate biomarkers can lead to a reduction in required enrollment in a study to show statistical significance. In turn, the decreased patient enrollment helps sponsors reduce costs and allows them to test several drugs with the same budget. In order to test our framework in an applied and relevant setting, we established from www.clinicaltrials.gov that for disease-modifying drugs the primary endpoint is change in ADAS-cog points at 18 months and that the trials enrolled on average 337 patients per treatment group. These disease-modifying AD trials use the inference on means statistical model. / (cont.) The standard deviation and the treatment effect of the primary endpoint variable (the change in ADAS-cog points at 18 months) are the main leverage factors that will influence the required enrollment (or sample size) in the trial. In a first step, we defined the baseline values for those main variables from published information on past or ongoing trials. Using that information, we conducted a theoretical exercise showing how much you needed to affect these variables in order to reduce enrollment by a factor of 5x, an important reduction in enrollment that could potentially realistically be achieved. In a second step, we looked in an applied setting at how well a selection of biomarkers in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database reduces the sample size by only selecting a sub population of the patients. Even with the limited data sample available on a preliminary basis from ADNI, we found that the biomarkers ABeta 1-42, ratio of Tau/ABeta 1-42, Apoe4 carriers on both genes, and average hippocampal volume show predictive power to identify change in ADAS-cog scores. When using criteria for these biomarkers to select a subpopulation we show that you can reduce the enrolled population by up to a factor 5.0x while decreasing your trial cost by up to 73% (corresponding to a $92M reduction out of $133M, the current Phase 3 costs of an 18 months diseases-modifying drug). Under the best scenario of these cost savings the sponsor can conduct pivotal trials for three drugs instead of only one. / (cont.) In a last step, the biomarker and combination of biomarkers associated with the enrollment benefit and the cost savings were assessed with additional criteria such as effect on restricted labeling, necessity for longitudinal screening or additional enrollment difficulties. Even after that analysis, several of the biomarkers stood out as very strong candidates to select for subpopulations in future disease-modifying trials and save costs. ADNI is an industry and NIH-sponsored initiative monitoring 800 normal, Mild Cognitive Impairment (MCI) and AD patients for up to three years with regular cognitive assessments and biomarker measurements. / by Hampus Hillerstrom. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references. / This thesis explores two aspects of small regulatory RNAs in mammals: (1) the genomic origin of mammalian piwi-interacting RNAs (piRNAs), (2) the evolutionary and functional implication of the seed-based target recognition mechanism of microRNAs (miRNAs). First, we participated in the discovery of mammalian piRNAs from adult rat testes. Our initial characterization of mammalian piRNAs by high-throughput sequencing revealed the peculiar features of their genomic origin: they predominantly derive from long singlestranded RNA precursors that are encoded at ~100 loci with no preferential association to repeat elements. Second, we measured the efficacy of polymorphic miRNA target sites in mammals. A large part of the miRNA-target recognition is determined by the 7-8-nt match between the seed region of miRNAs and the 3'UTR of mRNAs. Because of the small informational complexity of the specificity, spontaneous point mutations in 3'UTRs often create or disrupt miRNA target sites. The resulting polymorphisms in the target sites may contribute to gene expression diversity. By experimentally measuring the efficacy of such polymorphic target sites, we were able to conclude that between two unrelated mammalian individuals of the same species more than 100 genes are likely differentially regulated due to the target-site polymorphisms. Some of the expression diversity might translate into phenotypic diversity, providing substrates for the natural selection to act upon. We also constructed a miRNA library covering nearly all ~-16,000 theoretically possible seed sequences. Under the assumption that the functionality of a miRNA is approximately defined by the identity of the seed, the library is a resource that may enable the systematic exploration of the phenotypic consequences of nearly all possible functionally distinct miRNA species. / by Jinkuk Kim. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Physicians must often diagnose their patients using disease archetypes that are based on symptoms as opposed to underlying pathophysiology. The growing concept of "precision medicine" addresses this challenge by recognizing the vast yet fractured state of biomedical data, and calls for a patient-centered view of data in which molecular, clinical, and environmental measurements are stored in large shareable databases. Such efforts have already enabled large-scale knowledge advancement, but they also risk enabling large-scale misuse. In this thesis, I explore several statistical opportunities and challenges central to clinical decision-making and knowledge advancement with these resources. I use the inherited heart disease hypertrophic cardiomyopathy (HCM) to illustrate these concepts. HCM has proven tractable to genomic sequencing, which guides risk stratification for family members and tailors therapy for some patients. However, these benefits carry risks. I show how genomic misclassifications can disproportionately affect African Americans, amplifying healthcare disparities. These findings highlight the value of diverse population sequencing data, which can prevent variant misclassifications by identifying ancestry informative yet clinically uninformative markers. As decision-making for the individual patient follows from knowledge discovery by the community, I introduce a new quantity called the "dataset positive predictive value" (dPPV) to quantify reproducibility when many research teams separately mine a shared dataset, a growing practice that mirrors genomic testing in scale but not synchrony. I address only a few of the many challenges of delivering sound interpretation of genetic variation in the clinic and the challenges of knowledge discovery with shared "big data." These examples nonetheless serve to illustrate the need for grounded statistical approaches to reliably use these powerful new resources. / by Arjun Kumar Manrai. / Ph. D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 50-51). / The National Institutes of Health (NIH) has been the stalwart of research funding at universities and academic teaching hospitals. However, since the start of the last decade NIH funding has contracted in real terms. Anticipating future Federal Government fiscal austerity, the situation appears unlikely to improve and most likely will become worse. Local area teaching hospitals have explored other funding to support their large research infrastructure such as industry-sponsored research. This thesis qualitatively assessed whether the Federal Government and local area academic hospital fiscal data over the last six years support the hypothesis: Yes, industry funding has been received to support research at local area teaching hospitals to substitute for decreased availability of NIH funds. To test the hypothesis, Federal and local hospital fiscal data were extracted and statistical analysis was performed in three key areas to challenge the hypothesis and eliminate confounding data. First, is National Institutes of Health funding decreasing in real terms? Second, have local area teaching hospitals compensated by soliciting and receiving greater levels of industry sponsored research dollars? Third, has industry increased support in light of decreased NIH funding or are industry research commitments uncorrelated? The test questions were evaluated across two different hospitals and against various economic benchmarks. The hypothesis was rejected. Decreased NIH research funding granted to local academic hospitals has not caused a corresponding increase in industry sponsored research funding. Given the structural difficulties of industry and academic hospital collaboration, this likely impacts the level of industry sponsored research funding. Unfortunately, upcoming long-term Federal fiscal austerity may severely curtail NIH budgets. Academic hospitals will either need to consider greater industry collaboration or reduce the size and scope of their research activities. / by John A. Truesdell, Jr. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 139-145). / Since the voicing source is located between the lower and upper airways and has a high impedance, the resonances of the lower airway appear as pole-zero pairs in vowel spectra. These pole-zero pairs interact non-linearly with the vocal tract formants, producing narrow frequency bands within which formant structure is unstable. The broader frequency bands between lower airway resonances are thus potentially optimal for the reliable production and accurate perception of specific formant patterns. This possibility is explored from three directions. First, models of the lower airway are built and analyzed, and their effects on vowel spectra are characterized. Second, evidence for the non-linear interactions between formants and lower airway resonances is presented from a speech production study, and the relations between these non-linearities and certain distinctive feature contrasts are explored. Third, a speech perception experiment is carried out in which the identification of a vowel (which could be either [+back] or [-back]) is dependent upon the interaction of the second lower airway resonance (represented as a zero without an accompanying nearby pole) with the second formant. The results of these studies indicate that lower airway resonances do play a role in speech production and perception, and that further study is warranted. In addition, some potential applications to respiratory and vocal medicine are suggested. / by Steven Michael Lulich. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 136-138). / Increasing competition and specialization of firms in the life sciences industry has led to recognition of the need for collaboration. Bioclusters, the co-location of life sciences entities in a specific geographic area, have therefore emerged as a global trend. While it is assumed that such clusters allow stakeholders to realize synergies through participation and presence in the local area, the collaborative behavior within these clusters has yet to be explored. The goal of this study was to characterize the barriers and enablers of effective collaboration within bioclusters, and amongst their key stakeholder groups. This study directly compared the bioclusters of San Diego and Singapore to gain an understanding of their relative collaborative environments. San Diego, with cluster longevity of over 40 years, provided an example of organic growth, given its roots in entrepreneurial activities. The Singapore cluster, still in an embryonic state, has a history of organized growth due to the leadership, support, and funding of the Singaporean government. The study of clusters that differ in history of formation and longevity of presence provided the breadth of information needed for an effective comparison of their collaborative environments and approach to collaborative endeavors. / (cont.) Key stakeholder groups, namely academia, industry, finance, and government, were identified and interviews within each cluster were targeted accordingly. Eighteen interviews were conducted in San Diego and sixteen in Singapore. Through literature review, design of a detailed questionnaire, completion of 34 interviews, and analysis of the resulting data, an empirical assessment of the environment for collaboration within each biocluster was performed. Use of two scoring models provided an objective relative comparison of the clusters, serving as tools to view aggregated interview results. The first model measured the environment for and level of local collaboration and resulted in a Collaboration Score. The second model compared the process of engagement in collaborative endeavors, and resulted in a Formality of Approach Score. The scoring models were also used to compare the collaborative behavior of key stakeholder groups. Results from relative scoring models indicated a higher Collaboration Score for Singapore as compared to San Diego (p-value=0.0421), and a higher Formality of Approach Score for San Diego, trending toward significance. Aggregate analysis of key stakeholder groups found finance as the most collaborative, with a higher Collaboration Score when compared to industry, the least collaborative group (p-value=0.0189). / (cont.) A higher Formality of Approach Score was also seen for finance when compared to academia (p-value=0.0479). Other notable results include a greater degree of local competition within San Diego (p-value=0.0266) and a particularly low percentage of local industry collaborations in both bioclusters, when compared to academia (p-value=0.0002). The enablers of collaboration in the San Diego biocluster were identified as the entrepreneurial culture and the existence of top research institutes, and barriers were found to be the high level of competition amongst cluster members and the lack of local venture capital presence. The enablers in the Singapore biocluster were identified as the physical co-location of public and private entities in the Biopolis and the leadership and financial support provided by the Singaporean government, and barriers were the culture of risk aversion that exists in the cluster and the relatively few entrepreneurs, who often serve as a backbone for the creation of informal networks. A model for the development of a biocluster was also identified through a comparison of the cluster formation history of San Diego and Singapore. This model needs to be refined and further tested for general applicability, but does suggest a promising start. / (cont.) Collaborations are important for the continued cycle of innovation in the field of life sciences. Bioclusters provide a forum for these collaborations to occur. Promoting the enablers and removing the barriers increases the effectiveness of collaborations, enhancing the success of a biocluster and its member firms. / by Rupa Bahri. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2004. / Includes bibliographical references (leaves 134-151). / Focused ultrasound is currently being developed as a non-invasive thermal ablation technique for benign and cancerous tumors in several organ systems. Although these therapies are designed to ablate tissue purely by thermal means, cavitation, the formation and collapse of gas bubbles, can occur. These bubbles can be unpredictable in their timing and location and often interfere with thermal therapies. Therefore, focused ultrasound techniques have tried to avoid bubbles and their effects. However, gas bubbles in vivo have some potential useful features for therapy. They greatly enhance local ultrasound absorption, and can on their own induce mechanical damage to the tissue. In addition, bubble clouds can block ultrasound wave propagation, providing a means to protect vital tissues during ablation of nearby pathology. If induced and controlled properly, cavitation in focused ultrasound therapy could potentially be very beneficial. The first aim of this research is to design and test in vivo ultrasound exposures that induce cavitation at appropriate times and take advantage of their absorption enhancing properties. In addition, methods to monitor and control cavitation induction and the associated therapy will be investigated. Second, a theoretical bubble model and acoustic field simulations will be used to design optimal pressure fields which very tightly control the cavitation location. These models will also be used to investigate methods for reducing the acoustic powers needed to induce cavitation while preventing off focus cavitation. For the final phase of the research a multi-channel, multi-frequency ultrasound amplifier system capable of delivering optimal exposures via large scale phased array systems will be developed and tested. In / (cont.) total, the thesis research will justify applications for cavitation in ultrasound therapy, and develop the technology and methodology to optimally use cavitation and monitor its effects in vivo. / by Shunmugavelu D. Sokka. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2009. / Includes bibliographical references (p. 132-143). / Multi-drug resistant tuberculosis (MDR-TB) patients in resource-poor settings experience large delays in starting appropriate drug regimens and are often not monitored appropriately due to an overburdened health care system, communication delays, and missing or error-prone data. Medical information systems can be used to alleviate these problems by increasing the timeliness and quality of laboratory information available. The research reported in this thesis developed, implemented, and evaluated two such systems in the urban, resource-poor setting of Lima, Peru in institutions with and without internet. The first part addresses the electronic collection of tuberculosis (TB) laboratory information from multiple institutions without internet. A handheld computer-based system was developed and implemented. A cluster randomized controlled trial and before-and-after comparison showed that this system had a significant effect in reducing processing times from 23 to 8 days, the proportion of cultures with delays >90 days from 9.2% to 0.1%, the number of errors by 57.1%, and the work-hours necessary to process results by 60%. A cost and timeline framework was developed to allow other organizations in resource-poor settings to implement this technology. The second part addresses a web-based system, e-Chasqui, developed to provide electronic communication and reporting of TB laboratory information to health care personnel within institutions with internet. A cluster randomized controlled trial showed that access to e-Chasqui resulted in significantly less time to receipt of test results, a 56% reduction in tests taking over 60 days to arrive and a 98% reduction of results that never arrived, as well as a significantly faster time to culture conversion among patients in intervention versus control centers. / (cont.) These two parts describe verified medical informatics tools and an implementation methodology for settings both with and without internet connectivity. / by Joaquin Andres Blaya. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 131-147). / Prostate cancer persists as a major public health issue in the United States and remains the second leading cause of cancer death in men. Early detection and disease monitoring in prostate cancer can significantly improve a patient's prognosis. The advent of prostate-specific antigen (PSA) screening has allowed physicians to monitor the levels of a specific protein, or biomarker, as a correlate of disease progression. This thesis focuses on optical detection of prostate tumors through the development of biomarker-targeted molecular imaging probes. In the first part of this work, engineered human prostate cancer cell lines were developed and characterized to determine the dynamics of post-translational processing for PSA proteolytic activity and to establish potential small animal models for validating protease-activatable imaging probes. Target-activatable gold nanoparticle imaging probes that can be self-assembled in a one-step reaction were then developed to detect biomarker proteases in vivo. The activated probes demonstrated a 5 to 8-fold fluorescence signal amplification, extended circulation time, and high image contrast in a mouse tumor model. Lastly, differential phage display selection was performed on human prostate cancer cells with low and high metastatic potentials to (1) identify cell-surface biomarkers specific to highly aggressive tumors, and (2) develop molecular imaging probes for detecting prostate cancer metastases. / (cont.) One peptide, LN4P-1, demonstrated preferential binding to highly metastatic PC3M-LN4 cells and identified a highly expressed protein on their cell surface. Fluorescently labeled LN4P-1 was able to detect PC3MLN4 tumors in vivo. In summary, this thesis outlines the development of molecular imaging probes for targeting tumors both at the primary site, through evaluation of biomarker protease activity, and at the metastatic site, through affinity-based analysis of biomarker expression. / by Chunyao Jenny Mu. / Ph.D.