Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / 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. [73-74]). / Herceptin was the poster child of personalized medicine that brought forward the notion that contemporaneously developed companion diagnostics (CDx) could lead to more efficacious use of a cancer therapeutic in a selected population. Despite a gap of 12 years, the recent approvals of Zelboraf and Xalkori in quick succession by the FDA are a testament to the fact that the age of cancer therapeutics co-developed with a companion diagnostic is finally upon us. The purpose of this thesis was to test the hypotheses, that the trend for CDx based therapy launches in oncology is NOT headed towards a dramatic upturn in the next 5 years and in the view of biopharmaceutical executives - increasing price and market share of launched drugs are the dominant drivers for investing in companion diagnostics, and that the other features of CDx, such as improving the productivity of oncology drug development and reducing development costs are essentially dispensable. These hypotheses were tested using a study design that involved conducting a pilot study comprising of 18 interviews of stakeholders directly involved with the decision making of oncology drug development - to synthesize the extent of contemporaneously developed CDx to be launched with a cancer therapeutic in the coming 5 years. An analysis of the results obtained from the survey indicate, that a significant number of oncology drug launches within this decade would feature a co-developed companion diagnostic, and that despite challenges and initial trepidations over this business model - the higher probability of success, lower development costs, shorter time to market and pricing power associated with this approach, are incentives that are increasingly attracting more oncology firms to adopt this strategy for developing targeted therapeutics. Based on these findings, the original hypotheses were rejected. / by Anand Mehrotra. / S.M.

Thesis (Sc. D.)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Page 157 blank. Cataloged from PDF version of thesis. / Includes bibliographical references (p. 145-156). / Space radiation poses a significant hazard to astronauts on long-duration missions, and the low fluences of charged particles characteristic of this field suggest that bystander effects, the phenomenon in which a greater number of cells exhibit damage than expected based on the number of cells traversed by radiation, could be significant contributors to overall cell damage. The purpose of this thesis was to investigate bystander effects due to signaling between different cell types cultured within 2D and 3D tissue architectures. 2D bystander signaling was investigated using a transwell insert system in which normal human fibroblasts (A) and keratinocytes (K) were irradiated with 1 GeV/n protons or iron ions at the NASA Space Radiation Laboratory using doses from either 2 Gy (protons) or 1 Gy (iron ions) down to spacerelevant low fluences. Medium-mediated bystander responses were investigated using three cell signaling combinations. Bystander signaling was also investigated in a 3D model by developing tissue constructs consisting of fibroblasts embedded in a collagen matrix with a keratinocyte epidermal layer. Bystander experiments were conducted by splitting each construct in half and exposing half to radiation then placing the other half in direct contact with the irradiated tissue on a transwell insert. Cell damage was evaluated primarily as formation of foci of the DNA repair-related protein 53BP1. In the 2D system, both protons and iron ions yielded a strong dose dependence for the induction of 53BP1 in irradiated cells, while the magnitudes and time courses of bystander responses were dependent on radiation quality. Furthermore, bystander effects were present in all three cell signaling combinations even at the low proton particle fluences used, suggesting the potential importance of including these effects in cancer risk models for low-dose space radiation exposures. Cells cultured in the 3D constructs exhibited a significant reduction in the percentages of both direct and bystander cells positive for 53BP1 foci, although the qualitative kinetics of DNA damage and repair were similar to those observed in 2D. These results provide evidence that the microenvironment significantly influences intercellular signaling and that cells may be more radioresistant in 3D compared to 2D systems. / by Sarah B. Lumpkins. / Sc.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 34-35). / In this paper we evaluate how harmonization of patent laws in China and India to developed world standards has affected innovative research and development activity in the life sciences industry of those countries. The patents listed in the United States Patent and Trademark Office were used as a proxy to measure innovative activity. The number and types of patents filed over the period from 1976 through 2008 were analyzed for trends towards innovation. At a high level, we found that 'Drugs and Medical' account for only 6% of Chinese patents but make up 20% of the universe of Indian patents. When evaluating patent activity over time, we found that filings rose exponentially in the mid-nineties corresponding to the creation and implementation of product patent laws in both countries. India exhibited a much higher and steeper increase, likely due to its previously established capabilities as a generics manufacturer. When segmenting the data based on type of firms (academic, foreign multinationals and local private) we found that post product patent laws, local private firms exhibit more activity in India whereas local firms and multinationals show similar amounts of activity in China. In both countries, academic institutions show the greatest amount of activity compared to the multinationals and local private companies. We conclude that stronger IP laws have resulted in greater innovative activity as seen in the exponential rise in patent filings in the life sciences industry in both China and India. Although India has shown greater activity compared to China possibly due to its established capabilities in the generics space as a result of its protective patent regime prior to the harmonization. / by Meera S. Gupta. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 71-73). / The leading publicly traded pharmaceutical companies ("Big Pharma) in the US are facing a commercial crisis - their sales structure collectively consisting of more than 100,000 pharmaceutical sales representatives, originally setup to launch blockbusters, is suffering as a result of shrinking pipelines and low NME approvals. Although sales and marketing constitutes by far the largest corporate expense at 33% of revenues, sales productivity continues to decline. The goal of this study is to explore how pharmaceutical sales will change over the next 5 - 7 years and more specifically explore the role technology (including the internet) will play in the sales process. The study focuses on testing the perceptions of two key stakeholders -pharmaceutical executives and current medical students (future physicians) regarding the future of pharmaceutical sales process. Accordingly, 33 individuals were interviewed of which 18 were pharmaceutical executives and 15 were future physicians. The study tests three hypotheses: 1. Pharma executives believe that sales representative based detailing will continue to be the predominant method to engage and sell to physician customers while future physicians believe that technology will play a dominant role in the pharmaceutical detailing process. 2. Pharmaceutical executives agree that the most effective and ethical method to convey the benefits and challenges of an ethical pharmaceutical product are via a trained sales representative while future physicians believe that the sales representative does not effectively and ethically convey the merits of the relevant pharmaceutical therapy. 3. Person to person contact is not essential in conveying the merits of a particular ethical therapy - pharmaceutical executives disagree with this premise while future physicians agree. / (cont.) The data sets were compared using the following statistical tests: Yates' chi-square test, Armitage's chi-squared test and Two sample test of binomial proportions. In conclusion, the data showed that the perceptions of pharma executives and future physicians were in concurrence with each other. / by Rehan A. Khan. / S.M.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2001. / Includes bibliographical references (p. 223-242). / Atherosclerosis is characterized by local remodeling of arterial structure and distensibility. Developing lesions either progress gradually to compromise tissue perfusion or rupture suddenly to cause catastrophic myocardial infarction or stroke. Reliable measurement of changes in arterial structure and composition is required for assessment of disease progression. Non-invasive carotid ultrasound can image the heterogeneity of wall structure and distensibility caused by atherosclerosis. However, this capability has not been utilized for clinical monitoring because of speckle noise and other artifacts. Clinical measures focus instead on average wall thickness and diameter distension in the distal common carotid to reduce sensitivity to noise. The goal of our research was to develop an effective system for reliable regional structure and deformation measurements since these are more sensitive indicators of disease progression. We constructed a system for freehand ultrasound scanning based on custom software which simultaneously acquires real-time image sequences and 3D frame localization data from an electromagnetic spatial localizer. With finite element modeling, we evaluated candidate measures of regional wall deformation. / (cont.) Finally, we developed a multi-step scheme for robust estimation of local wall structure and deformation. This new strategy is based on a directionally-sensitive segmentation functional and a motion-region-of-interest constrained optical flow algorithm. We validated this estimator with simulated images and clinical ultrasound data. The results show structure estimates that are accurate and precise, with inter- and intra-observer reproducibility surpassing existing methods. Estimates of wall velocity and deformation likewise show good overall accuracy and precision. We present results from a proof-of-principle evaluation conducted in a pilot study of normal subjects and clinical patients. For one example, we demonstrate the combination of 2D image processing with 3D frame localization for visualization of the carotid volume. With slice localization, estimates of carotid wall structure and deformation can be derived for all axial positions along the carotid artery. The elements developed here provide the tools necessary for reliable quantification of regional wall structure and composition changes which result from atherosclerosis. / by Raymond C. Chan. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 281-301). / This thesis will explore the use of Transcranial Magnetic Stimulation (TMS) and Transcranial DC Stimulation (tDCS) as modalities for neuropathology treatment by means of both experimental and modeling paradigms. The first and primary modality that will be analyzed is Transcranial Magnetic Stimulation (TMS). TMS is a technique that uses the principle of electromagnetic induction to focus induced currents in the brain and modulate cortical function. These currents can be of sufficient magnitude to depolarize neurons, and when these currents are applied repetitively (repetitive Transcranial Magnetic Stimulation (rTMS)) they can modulate cortical excitability, decreasing or increasing it, depending on the parameters of stimulation. This thesis will explore important facets of the electromagnetic field distributions and fundamental electromagnetic interactions to lay the foundation for future development of a more complete neural model and improved stimulation techniques. First, TMS will be analyzed as a technique used in normal healthy subjects. Finite element modeling (FEM) studies will be explored for realistic healthy human head models with a particular focus placed on the TMS induced cortical currents and their dependency on coil position, normal tissue anatomy, and the electromagnetic tissue properties. / (cont.) This component of the thesis will also include experimental work focused on exploring the in-vivo tissue conductivity and permittivity values used in TMS studies and their impact on stimulation (including a detailed literature review). The next component of the thesis will explore the use of TMS in subjects suffering from various pathologies. The first pathological condition that will be analyzed is cortical stroke. FEM studies will be evaluated and compared to the healthy head models to assess how the cortical modifications brought on at an infarction site can alter the TMS induced current densities. We will also include a laboratory study that assesses the efficacy of TMS in stroke treatment, where repetitive TMS (rTMS) was applied to the unaffected hemisphere to decrease inter-hemispheric inhibition of the lesioned hemisphere and improve motor function in stroke patients. Next, the use of TMS in conditions of brain atrophy will be assessed through modeling analyses. This component will also include an evaluation of the clinical work in the field and ways in which the current density alterations caused by the atrophy have led to clinical misconceptions. Transcranial DC Stimulation (tDCS) will be the second modality analyzed through modeling and experimental work. / (cont.) In tDCS, the cerebral cortex is stimulated through a weak dc current in a non-invasive and painless manner and can modulate cortical excitability like TMS. We will define finite element head models of tDCS for both normal and pathologic cases and evaluate the use of tDCS in the clinic in a stroke treatment experiment (analogous to the one completed with TMS). Finally, we will assess and compare these forms of brain stimulation to other forms of neurological treatment and conclude with proposed future improvements to the field of non-invasive brain stimulation. / by Tim Wagner. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 115-120). / Microfabricated transducers have enabled new approaches for detection of biomolecules and cells. Integration of electronics with these tools simplify systems and provide platforms for robust use outside of the laboratory setting. Suspended microchannel resonators (SMRs) are sensitive microfluidic platforms used to precisely measure the buoyant mass of single cells and monolayers of protein in fluid environments. Conventionally, micro cantilever deflection is measured by the optical-lever technique, wherein a laser beam is reflected off the cantilever onto a position sensitive photodiode. This thesis introduces microchannel resonators with electronic readout, eliminating the use of external optical components for resolving the sensor's resonant frequency. Piezo resistors have been fabricated on SMRs through ion implantation integrated with the existing SMR fabrication process. We fabricated two designs: one with a cantilever length of 210 pm and resonant frequency of -347 kHz, and the other with a cantilever length of 406 pm and resonant frequency of ~92 kHz. The work here builds upon knowledge of signal transduction from static and dynamic cantilever based sensors because the piezo resistors are implemented on vacuum encapsulated devices containing fluid. Electronic readout is shown to resolve the microchannel resonance frequency with an Allan variance of 5 x 10-18 (210 pm) and 2 x 1017 (406 pm) using a 100ms gate time, corresponding to a mass resolution of 0.1 and 0.4 fg respectively. This mass resolution calculated from piezoresistive readout frequency stability, is approximately 3X better than optical readout for the 210 pm device and 1.3X for the 406 pm device using the same gate time. Resolution is expected to improve with further optimization of the system. To demonstrate the readout, histograms of the buoyant masses of a mixture of size standard polystyrene beads (with nominal diameters 1.6, 1.8, and 2.0 pm) and budding yeast cells were made. / Ph.D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2001. / Vita. / Includes bibliographical references (p. 127-138). / The universality of many aspects of music, such as octave-based tuning systems and the use of dissonance and consonance to create harmonic tension and resolution, suggests that their perception may have fundamental neurophysiological bases. Thus, music provides a natural set of stimuli and associated percepts with which the auditory system can be studied. Here, we seek correlates of pitch, the essential element of melody, and roughness, a primary component of dissonance, in responses of single auditory neurons in anesthetized cats. Pitch, the perceived highness or lowness of sound, is generally thought to be based on a neurophysiological representation of frequency. Because neural responses (spikes) phaselock to low stimulus frequencies, interspike intervals (ISIs) reflect the stimulus period and can be used to estimate frequency. To rigorously test this potential code for pitch, we look for correlates of pitch under conditions where the percept deviates from a simple function of frequency. One such condition is the octave enlargement effect, listeners' preference for pure-tone octave ratios slightly greater than 2:1. Another is the pitch of a complex tone missing the fundamental frequency: the pitch matches that of the missing fundamental even when different harmonics are presented to opposite ears. We show that a correlate of the octave enlargement effect exists in ISIs of auditory nerve (AN) fibers and a correlate of the missing-fundamental pitch exists in ISIs of neurons in the inferior colliculus, the principal auditory nucleus of the midbrain. Results also reveal greater degradation of pitch representation at the midbrain compared to the periphery. / (cont.) Roughness, the sensation of temporal envelope fluctuations in the range of 20-200 Hz, is often equated with sensory dissonance. Here we examine IC neural responses for correlates of sensory dissonance. We show that sensory dissonance correlates with discharge rate fluctuations of all IC neurons and with average rates of a subset of IC neurons which only respond at the onset of pure-tones. Results indicate that IC neurons are specifically important for the coding of the temporal envelope. Our findings illustrate the complexity and specificity of auditory neural processing in the brainstem and midbrain and show that percepts generally considered to be high order, such as the dissonance of musical intervals, have direct correlates in neural responses in the midbrain. More generally they show that the auditory system performs processing important for music at multiple time scales. / by Martin Franciscus. / Ph.D.

Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 102-110). / When making daily decisions, people naturally ask two questions: how soon can I make a decision, and is it a good decision? In experimental setting, humans can subjectively yet quantitatively assess choice confidence (i.e. how good) based on their perceptual precision even when a decision is made without an immediate reward or feedback. Such choice confidence has been shown to have a non-monotonic relationship with decision time (i.e. how soon), such that choice confidence can be correlated either positively or negatively with decision time depending on how decision time is constrained. However, the neural mechanisms underlying the interaction between choice confidence and decision time during perceptual decision-making are still unclear. Hence, the goals of this research were to (1) develop dynamic computational models and to (2) find neural representations of choice confidence in human scalp potentials. The dynamic models of choice confidence were developed by merging two parallel conceptual frameworks of decision-making, signal detection theory and sequential analyses (i.e., drift diffusion model). Specifically, in order to capture the end-point statistics of binary choice and confidence, we built on a previous study that defined choice confidence in terms of psychophysics derived from signal detection theory. At the same time, we augmented this mathematical model to include accumulator dynamics of a drift-diffusion model to characterize the time-dependence of choice behaviors in a standard forced-choice paradigm. Twelve human subjects performed a subjective visual vertical task, simultaneously reporting binary orientation choice and probabilistic confidence. Both binary choice and confidence experimental data displayed statistics and dynamics consistent with both signal detection theory and evidence accumulation, respectively. Specifically, the computational simulations showed that the unbounded evidence accumulator model fits the confidence data better than the classical bounded model while bounded and unbounded models were indistinguishable for binary choice data. These results suggest that the brain can utilize mechanisms consistent with signal detection theory to assess confidence when observation duration is externally controlled. As a neural mechanism that binds choice action and confidence, a fronto-parietal network has been implicated. Such bi-local neural circuitry is consistent with dual-route model of metacognition, in which the prefrontal cortex supervises and evaluates objectlevel parietal cortex. However, the neural dynamics underlying the interaction between choice confidence and decision time in the fronto-parietal network during the perceptual decision-making have yet to be elucidated. Here we show in fifteen human subjects that choice confidence contributes to frontal event-related potential (ERP) during a predecisional stage when choice accuracy is emphasized over speed during a free response task. We found that the second positive peak, particularly the curvature, of the stimuluslocked frontal ERP at 400-600ms covaries with confidence while the amplitude of the centro-parietal ERP increases with faster decision response time during the same time interval. This finding provides evidence for a causal role of confidence in perceptual decision-making, complementing earlier ERP evidence supporting a retrospective role. Altogether, these results suggest that an internal representation of choice confidence evolves concurrently with choice action prior to reporting a decision. Furthermore, the non-monotonic dynamics of confidence arise from its dual roles that may be determined by the prior expectation of decision time constraint. In other words, the causal role of confidence may underlie the negative correlations between choice confidence and decision time behaviors while the retrospective role may underlie the positive correlations. / by Koeun Lim. / Ph. D. in Biomedical Engineering

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Includes bibliographical references (leaves 21-22). / Clinical documentation by physicians and nurses has struggled to evolve with advancing technology and societal requirements. Originally designed as a physician's personal notes for a patient, the modern medical record functions as a patient record, communication tool between providers, and instrument for financial reimbursement. Technology has played a pivotal part in advancing the role of the medical record. Advantages and disadvantages inherent in the introduction of each new technology have prompted much debate, but none more than the introduction of electronic documentation systems within electronic medical records. Electronic systems provide clear advantages of information exchange as well as decision and diagnostic support. They have also proven quite controversial, particularly in the initial implementation stages. One aspect of electronic documentation, electronic copying and pasting, provides a tool for the clinician that is not clearly beneficial or detrimental, with proponents on each side. In this paper we explore the social, economic, and legal issues surrounding electronic copying and pasting in clinical documentation, review the literature on this subject, and propose a model for future research in this topic to help shape how clinicians use and process patient information from multiple sources. / by Michael Jernigan. / S.M.