Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references. / Drug-eluting stents (DES) virtually eradicate the clinical phenomena of vessel restenosis; yet, they also increase the short and long term risks for stent thrombosis. To improve their safety and efficacy, it is critical to examine factors that alter local biologic outcome. The central hypothesis of this thesis is that local efficacy and toxicity are in part determined by the duration of drug exposure and local arterial drug concentrations. This thesis investigates how factors both intrinsic and extrinsic to the device impact local intravascular drug delivery. Computational models of local fluid mechanics and drug transport were formulated to study how arterial drug uptake is modulated by local blood flow, stent placement, administered drug dose and release kinetics, and the evolving local vascular response to the device. Lumenally flowing blood around stent struts was capable of transporting drug to the arterial wall in the presence of both single and multiple configurations of drug eluting stent struts. The extent of blood flow mediated arterial drug delivery depended upon the rate of drug release and administered dose. Slow drug release led to sustained, low magnitude drug uptake; exceedingly fast release resulted in transient and minimal tissue absorption due to rapid drug depletion. / (cont.) Drug release over several minutes maximized peak arterial drug concentrations, though arterial drug levels were not sustained. Mural thrombus did not alter the rate of drug release from a stent; however, clots increased local drug availability and reduced the extent of drug washout. Subsequently, variability in mural thrombi formation caused fluctuations in arterial drug levels. Computational modeling revealed that free diffusion of hydrophobic drugs was slower than experimental arterial drug absorption. Subsequently, a novel mechanism for arterial drug transport has been proposed in which drug diffuses faster through the arterial wall due to its association with carrier proteins. Within this thesis, we have elucidated that device, patient, and physician-dependent device implantation are among the factors governing arterial drug deposition; these subsequently dictate local efficacy and toxicity. Thus, rational design of improved local therapeutics requires consideration of how multiple interrelated factors intrinsic and extrinsic to the device determine local efficacy and toxicity. / by Brinda Balakrishnan. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 74-76). / Background: Estimation of cost-effectiveness of a therapy as compared with another, in healthcare, is often based on a single perspective and a single time horizon. In this thesis, I explored methods of extrapolating the survival effect of different interventions and the effect of time horizon on incremental cost-effectiveness ratios when comparing two strategies. Methods: Two strategies for a patient are compared: new or usual treatment. A hypothetical model based on US life tables (for a 64-year old) assumed that the new and usual treatment strategies resulted in patient survivals identical to a person who is 5 and 10 years older, respectively, than the patient's chronologic age. The hazard rates over time were calculated and transformed to linear equations for least-squares linear regression to fit exponential, linear exponential, Weibull and Gompertz distributions. The survival model yielding the maximal likelihood estimate was extrapolated over different time horizons: 5, 10 and 15-year in addition to lifetime. In addition, I extracted survival data from a published trial evaluating thrombolysis in patients with myocardial infarction and applied this methodology over different time horizons. / (cont.) Finally, I developed a matrix of incremental cost-effectiveness ratios over different time horizons, based on an overview model, examining alternative assumptions when the cumulative difference in cost and effectiveness of the two strategies: 1) decrease 2) remain constant or 3) increase. I used a statistical programming language "R" for evaluation and analysis. Results: When considering a US life-table based hypothetical model, Gompertz curve was the best-fitting model. A linear-exponential model had the best fit when considering a survival model of thrombolysis patients. A matrix of incremental cost-effectiveness ratios with decreasing, constant and increasing cumulative difference in cost and effectiveness showed considerable change in incremental cost-effectiveness ratios over different time horizons. The magnitude of effect of time horizon was flattened with increasing discount rate for future cumulative differences in cost and effectiveness. With the exception of similarly behaving and proportionate cumulative difference in cost and effectiveness leading to unchanged incremental cost-effectiveness ratios, incremental cost-effectiveness ratios decreased when cumulative difference in effectiveness increased and increased when cumulative difference in effectiveness decreased, irrespective of behavior of cumulative difference in costs. / (cont.) Conclusions: When conducting cost-effectiveness analysis of two competing strategies, choice of time horizon has a substantial effect. Incremental cost-effectiveness ratio changes considerably with changes in duration of time horizon. Discounting flattens the effect of time horizon in cost-effectiveness analysis. Care must be taken in choosing the time horizon in a cost-effectiveness analysis and alternative time horizons must be evaluated in all cost-effectiveness analyses. / by Manu Sondhi. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references. / In vivo reflectance and fluorescence spectra were collected from patients with oral lesions, as well as healthy volunteers, in order to evaluate the potential of spectroscopy to serve as a non-invasive tool for the detection oral cancer. A total of 710 spectra were analyzed from 79 healthy volunteers, and 87 spectra from 67 patients. Physical models were applied to the measured spectral data in order to extract quantitative parameters relating to the structural and biochemical properties of the tissue. Data collected from healthy volunteers were used to characterize the relationship between the spectral parameters and tissue anatomy. Diagnostic algorithms for distinguishing various lesion categories were then developed using data collected from patients. The healthy volunteer study demonstrated that tissue anatomy has a strong influence on the spectral parameters. Anatomic sites could be easily distinguished from each other despite the apparent overlap in their parameter distributions. In particular, keratinized sites (gingiva and hard palate) were significantly distinct from other anatomic sites. The results of this study provide strong evidence that a robust and accurate spectroscopic based diagnostic algorithm for oral cancer needs to be applied in a site specific manner. Spectral diagnostic algorithms were developed using the data collected from patients, in combination with the data collected from healthy volunteers. The diagnostic performance of the algorithms was evaluated using the area under a receiver operator characteristic curve (ROC-AUC) and the sensitivity and specificity. The diagnostic algorithms were most successful when developed and applied to data collected from a single anatomic site or spectrally similar sites, and when distinguishing visibly normal mucosa from lesions. / (cont.) ROC-AUC values of >0.90 could be achieved for this classification. Spectral algorithms for distinguishing benign lesions from dysplastic/malignant lesions were successfully created for the lateral surface of the tongue (ROC-AUC =0.75) and for the combination of the floor of the mouth and ventral tongue (ROC-AUC =0.71). / by Sasha Alanda McGee. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 62-65). / Alternative pre-messenger RNA splicing is a crucial step in eukaryotic gene expression, and therefore it is subject to tight regulation. Given its importance in conferring protein diversity, alternative splicing is sensitive to changes in cellular states including malignancy. We present a new paradigm by which to quantitatively study the alternative splicing of any molecule through the presented methods of quantitative exon profiling and quantitative isoform profiling which take advantage of a single-molecule based technology [Mit99]. Furthermore, we extend this paradigm to include a novel unified platform-called Isoform Convergence-to qualify particular isoforms as candidate diagnostic markers, potential therapeutic targets, and perhaps even as precursor therapeutics themselves. We apply this paradigm to quantitatively investigate the alternative splicing of CD44 in two leukemias. CD44 is an alternatively spliced cell surface receptor, which is generally implicated in cancer though the specifics are mired in controversy. In this work, we suggest several corrections to previously made claims about the presence of specific CD44 exons and of specific CD44 isoforms in leukemia as well as in non-diseased cells. / (cont.) Furthermore, we provide not only the first comprehensive characterization of CD44's (or any molecule's) alternative exon splicing in human cells, but also its resulting quantities of exons and isoforms to an average resolution on the order of 1.E+06 molecules. Finally, we identify specific isoforms in each leukemia that may serve as candidate markers or possibly as therapeutic targets. / by Chris Varma. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 123-126). / Acoustic parameters that differentiate between primary stress and non-primary full vowels were determined using two-syllable real and novel words and specially constructed novel words with identical syllable compositions. The location of the high focal pitch accent within a declarative carrier phrase was varied using an innovative object naming task that allowed for a natural and spontaneous manipulation of phrase-level accentuation. Results from male native speakers of American English show that when the high focal pitch accent was on the novel word, vowel differences in pitch, intensity prominence, and amplitude of the first harmonic, H1 * (corrected for the effect of the vocal tract filter), accurately distinguished full vowel syllables carrying primary stress vs. non-primary stress. Acoustic parameters that correlated to word stress under all conditions tested were syllable duration, HI*-A3*, as a measurement of spectral tilt, and noise at high frequencies, determined by band-pass filtering the F3 region of the spectrum. Furthermore, the results indicate that word stress cues are augmented when the high focal pitch accent is on the target word. / (cont.) This became apparent after a formula was devised to correct for the masking effect of phrase-level accentuation on the spectral tilt measurement, Hi *-A3*. Perceptual experiments also show that male native speakers of American English utilized differences in syllable duration and spectral tilt, as controlled by the KLSYN88 parameters DU and TL, to assign prominence status to the syllables of a novel word embedded in a carrier phrase. Results from this study suggest that some correlates to word stress are produced in the laryngeal region and are due to vocal fold configuration. The model of word stress that emerges from this study has aspects that differ from other widely accepted models of prosody at the word level. The model can also be applied to improve the prosody of synthesized speech, as well as to improve machine recognition of speech. / by Anthony O. Okobi. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Includes bibliographical references (p. 69-83). / The use of functional magnetic resonance imaging (fMRI) to study the non-human primate brain has been developed over the past decade. Primate fMRI has many attractive features: it allows validation of previous homology assumptions between humans and monkeys, provides a model to combine imaging with invasive techniques to directly manipulate the brain, and can guide other modalities, such as electrophysiology, to new areas of interest. The frontal eye field (FEF) is a well-studied node in the oculomotor network, involved in visual target selection and saccade planning. Recent evidence has implicated FEF as a possible source of feedback signals that modulate visually-driven activity in posterior cortical areas, such as during the deployment of spatial attention. The goals of this thesis were extend the unique aspects of primate fMRI by combining it with simultaneous, intra cortical microstimulation (EM), and to use these new methods to measure how local, artificially-increased FEF output could modulate visually-driven fMRI activity in earlier cortical regions. The first outcome of this thesis was a novel form of functional tractography. FEF-EM below the threshold needed to evoke saccades yielded robust, focal fMRI activity in cortical and sub cortical structures connected with FEF. The second outcome was a demonstration that subthreshold FEF-EM produced retinotopically-specific enhancement and suppression of the representation of a stimulus presented at the saccadic endpoint, or movement field (MF), of the stimulated FEF site. Modulation occurred at multiple levels of the visual system and the signals presumably causing it appeared to be gated in the earliest cortical areas by bottom-up activity. The third outcome was a characterization of how stimulus intensity altered these modulations. / (cont.) The luminance contrast of a stimulus presented in the MF was systematically varied to generate contrast response functions for many cortical areas, which were compared with existing data. Sub-threshold FEF-EM increased fMRI activity for the lowest contrasts and had little or even a suppressive influence at the highest contrasts, mainly in support of a contrast rather than activity gain effect. From these data, a simple spatial model explaining the interaction between bottom-up and top-down signals from the FEF was constructed, which could guide future psychophysical and electrophysiological experiments. The final outcome was a demonstration that artificially-increased FEF output could alter stimulus selectivity in visual cortex independent of stimulus saliency. This suggests that FEF relays not only spatial but also feature-relevant information to specific visual cortical areas. / by Leeland Bruce Ekstrom. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (leaves 39-41). / Here we describe an experimental method for measuring the acoustic transmission matrix of the middle-ear using otoacoustic emissions. The experiment builds on previous work that uses distortion product otoacoustic emissions (DPOAEs) as an intracochlear sound source to drive the middle-ear in reverse. This technique eliminates the complications introduced by needing to place an acoustic transducer inside the cochlea. Previous authors have shown how the complete 4x3 system response matrix, with its 12 unknowns, can be simplified to a 2x2 transmission matrix by de-coupling the middle-ear cavity and assuming the cochlear fluids are incompressible. This simplified description of middle-ear mechanics assumes that the input-output response at the tympanic membrane and stapes footplate is linear, one dimensional and time invariant. The technique allows for estimating the acoustic pressure and volume velocity at the tympanic membrane and the volume velocity of the stapes footplate, in both the forward and reverse direction, and under different boundary conditions at the stapes. The technique was applied to deeply anesthetized cats with widely opened middle-ear cavities over a frequency range of 200Hz to 10kHz. Results on three animals are reported and generally agree with previous data and a published middle-ear model. / by Antonio John Miller. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (leaves 37-40). / Since the Bayh-Dole Act of 1980, the commercialization of ideas generated in academia has driven significant startup activity and expansion in the life sciences. This commercial transformation has been shown by others to be concentrated among a relatively small number of elite academic institutions. However, within these institutions, we find that a small number of prestigious scientists are disproportionately responsible for entrepreneurial and commercial activity. To date, limited research has been conducted which aims to understand the characteristics of such serial scientist-entrepreneurs or their significance in early commercial ventures. This study identifies and characterizes 18 serial scientist-entrepreneurs (defined as faculty who have founded or served on the board of directors of 3 or more startups) on the basis of academic impact, patenting, and social network centrality, as compared to their first-time entrepreneur (i.e., faculty who founded or directed 1-2 companies) and noncommercial peers. These individuals constitute a subset of 66 scientist-entrepreneurs from a population of the 493 scientists who served as faculty in life sciences-related departments at MIT, during the period of 1981 to 2005 (representing the primary commercialization period for biotechnology). / (cont.) The thesis highlights three key findings. First, the subset of 18 serial scientist-entrepreneurs founded or directed two-thirds of all startup ventures associated with the entire population thus underscoring the significant "skew" in commercial activities. Furthermore, empirical analyses revealed that these serial scientist-entrepreneurs had significantly higher academic impact (i.e., "academic prestige"), as measured by citations to their work, as compared to first-time entrepreneurs and noncommercial scientists. Perhaps not surprisingly, they also had significantly higher numbers of issued U.S. patents, compared to first-time entrepreneurs. Second, the serial scientist-entrepreneurs developed robust relationships with a small group of venture capital investors, who have repeatedly funded their companies. Several of these serial scientist-entrepreneurs retained central positions in the social network of faculty entrepreneurs, potentially brokering and accelerating entrepreneurial activity, including scientific advisory board membership, within the community. These findings suggest that serial scientist-entrepreneurs play a vital role in contributing reputation, deep technical insight, access to intellectual property, and relationship networks to startup life sciences ventures. / (cont.) It remains for additional research to determine whether the active involvement of serial scientist-entrepreneurs has resulted in enhanced startup value or performance. / by Eugene Chiu. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references. / The current clinical standard for cervical cancer diagnosis is colposcopy, a procedure that involves visual inspection and biopsy of at-risk tissue, followed by histopathology. The major objective of colposcopy is detection of high-grade squamous intraepithelial lesions (HSIL), which are precancerous lesions with high risk of progression. Colposcopy, even when conducted by experts, is subject to significant diagnostic variability. The aim of the work presented in this thesis was to develop a non-invasive clinical tool for detection of cervical HSIL and for guiding the biopsy during colposcopy. Previously we have developed a contact-probe portable instrument for tissue reflectance and fluorescence collection, and spectral analysis models to extract and quantify biochemical and structural features of tissue to provide disease state assessment. In this thesis we further refine the instrumentation and spectral analysis models and conduct the clinical in vivo studies. The clinical in-vivo study showed cervical anatomy was a confounder to diagnostic algorithms that treat cervix as spectroscopically uniform. We used complex instrumentation to comprehensively study cervical tissue and found that scattering alone was sufficient to identify HSIL. We developed an accurate algorithm based on tissue scattering for detection of HSIL in the cervical transformation zone, an area where vast majority of cervical lesions arise. We further successfully extended our point-probe technique into the imaging mode, to provide the wide-area surveillance capability. / (cont.) The ongoing imaging clinical in-vivo feasibility study demonstrates spectroscopic contrast between cervical HSIL and non-HSIL tissue and is consistent with findings of the contact-probe study. The future steps include diagnostic accuracy assessment of the imaging technique, and if proven successful, a clinical study to evaluate the performance of spectroscopy-guided biopsy. / by Jelena Mirković. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 53-58). / There is a strong correlation between the membrane fluctuations and the material properties of living cells. The former, consisting of submicron displacements, can be altered by changing the cells' pathophysiological conditions. It is our hypothesis that the material properties of cells can be retrieved when we quantify cell membrane fluctuation and combine that result with an appropriate physical model. We have developed: (1) an optical imaging technique to noninvasively quantify membrane fluctuations in red blood cells at the nanometer and millisecond scales; and (2) a model to retrieve the material properties of red blood cell membrane. The technique employs laser interferometry and provides full-field quantitative topographical information of living cells with unprecedented stability. Integration with the mathematical model provides the specific material properties from individual cell membrane fluctuations: shear modulus of the membrane; bending modulus; and viscosity of the cytoplasm. Employing these methods, we have systemically studied the material properties of human red blood cells altered by various pathophysiological conditions: morphological transition of red blood cell; parasitization by the P. falciparum parasites; and metabolic remodeling of the membrane driven by Adenosine-5'- triphosphate (ATP). We envision that this investigation could offer a means to link cell membrane fluctuations with the pathological conditions that lead to human disease states by quantitatively providing the alternation in material properties. A clear understanding of the mechanical alteration of red blood cells is important to studying the human diseases which cause their infection. / Ph.D.