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Description
In an effort to begin validating the large number of discovered candidate biomarkers, proteomics is beginning to shift from shotgun proteomic experiments towards targeted proteomic approaches that provide solutions to automation and economic concerns. Such approaches to validate biomarkers necessitate the mass spectrometric analysis of hundreds to thousands of human

In an effort to begin validating the large number of discovered candidate biomarkers, proteomics is beginning to shift from shotgun proteomic experiments towards targeted proteomic approaches that provide solutions to automation and economic concerns. Such approaches to validate biomarkers necessitate the mass spectrometric analysis of hundreds to thousands of human samples. As this takes place, a serendipitous opportunity has become evident. By the virtue that as one narrows the focus towards "single" protein targets (instead of entire proteomes) using pan-antibody-based enrichment techniques, a discovery science has emerged, so to speak. This is due to the largely unknown context in which "single" proteins exist in blood (i.e. polymorphisms, transcript variants, and posttranslational modifications) and hence, targeted proteomics has applications for established biomarkers. Furthermore, besides protein heterogeneity accounting for interferences with conventional immunometric platforms, it is becoming evident that this formerly hidden dimension of structural information also contains rich-pathobiological information. Consequently, targeted proteomics studies that aim to ascertain a protein's genuine presentation within disease- stratified populations and serve as a stepping-stone within a biomarker translational pipeline are of clinical interest. Roughly 128 million Americans are pre-diabetic, diabetic, and/or have kidney disease and public and private spending for treating these diseases is in the hundreds of billions of dollars. In an effort to create new solutions for the early detection and management of these conditions, described herein is the design, development, and translation of mass spectrometric immunoassays targeted towards diabetes and kidney disease. Population proteomics experiments were performed for the following clinically relevant proteins: insulin, C-peptide, RANTES, and parathyroid hormone. At least thirty-eight protein isoforms were detected. Besides the numerous disease correlations confronted within the disease-stratified cohorts, certain isoforms also appeared to be causally related to the underlying pathophysiology and/or have therapeutic implications. Technical advancements include multiplexed isoform quantification as well a "dual- extraction" methodology for eliminating non-specific proteins while simultaneously validating isoforms. Industrial efforts towards widespread clinical adoption are also described. Consequently, this work lays a foundation for the translation of mass spectrometric immunoassays into the clinical arena and simultaneously presents the most recent advancements concerning the mass spectrometric immunoassay approach.
ContributorsOran, Paul (Author) / Nelson, Randall (Thesis advisor) / Hayes, Mark (Thesis advisor) / Ros, Alexandra (Committee member) / Williams, Peter (Committee member) / Arizona State University (Publisher)
Created2011
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Description
Signal processing techniques have been used extensively in many engineering problems and in recent years its application has extended to non-traditional research fields such as biological systems. Many of these applications require extraction of a signal or parameter of interest from degraded measurements. One such application is mass spectrometry immunoassay

Signal processing techniques have been used extensively in many engineering problems and in recent years its application has extended to non-traditional research fields such as biological systems. Many of these applications require extraction of a signal or parameter of interest from degraded measurements. One such application is mass spectrometry immunoassay (MSIA) which has been one of the primary methods of biomarker discovery techniques. MSIA analyzes protein molecules as potential biomarkers using time of flight mass spectrometry (TOF-MS). Peak detection in TOF-MS is important for biomarker analysis and many other MS related application. Though many peak detection algorithms exist, most of them are based on heuristics models. One of the ways of detecting signal peaks is by deploying stochastic models of the signal and noise observations. Likelihood ratio test (LRT) detector, based on the Neyman-Pearson (NP) lemma, is an uniformly most powerful test to decision making in the form of a hypothesis test. The primary goal of this dissertation is to develop signal and noise models for the electrospray ionization (ESI) TOF-MS data. A new method is proposed for developing the signal model by employing first principles calculations based on device physics and molecular properties. The noise model is developed by analyzing MS data from careful experiments in the ESI mass spectrometer. A non-flat baseline in MS data is common. The reasons behind the formation of this baseline has not been fully comprehended. A new signal model explaining the presence of baseline is proposed, though detailed experiments are needed to further substantiate the model assumptions. Signal detection schemes based on these signal and noise models are proposed. A maximum likelihood (ML) method is introduced for estimating the signal peak amplitudes. The performance of the detection methods and ML estimation are evaluated with Monte Carlo simulation which shows promising results. An application of these methods is proposed for fractional abundance calculation for biomarker analysis, which is mathematically robust and fundamentally different than the current algorithms. Biomarker panels for type 2 diabetes and cardiovascular disease are analyzed using existing MS analysis algorithms. Finally, a support vector machine based multi-classification algorithm is developed for evaluating the biomarkers' effectiveness in discriminating type 2 diabetes and cardiovascular diseases and is shown to perform better than a linear discriminant analysis based classifier.
ContributorsBuddi, Sai (Author) / Taylor, Thomas (Thesis advisor) / Cochran, Douglas (Thesis advisor) / Nelson, Randall (Committee member) / Duman, Tolga (Committee member) / Arizona State University (Publisher)
Created2012
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Description
Cancer claims hundreds of thousands of lives every year in US alone. Finding ways for early detection of cancer onset is crucial for better management and treatment of cancer. Thus, biomarkers especially protein biomarkers, being the functional units which reflect dynamic physiological changes, need to be discovered. Though important, there

Cancer claims hundreds of thousands of lives every year in US alone. Finding ways for early detection of cancer onset is crucial for better management and treatment of cancer. Thus, biomarkers especially protein biomarkers, being the functional units which reflect dynamic physiological changes, need to be discovered. Though important, there are only a few approved protein cancer biomarkers till date. To accelerate this process, fast, comprehensive and affordable assays are required which can be applied to large population studies. For this, these assays should be able to comprehensively characterize and explore the molecular diversity of nominally "single" proteins across populations. This information is usually unavailable with commonly used immunoassays such as ELISA (enzyme linked immunosorbent assay) which either ignore protein microheterogeneity, or are confounded by it. To this end, mass spectrometric immuno assays (MSIA) for three different human plasma proteins have been developed. These proteins viz. IGF-1, hemopexin and tetranectin have been found in reported literature to show correlations with many diseases along with several carcinomas. Developed assays were used to extract entire proteins from plasma samples and subsequently analyzed on mass spectrometric platforms. Matrix assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) mass spectrometric techniques where used due to their availability and suitability for the analysis. This resulted in visibility of different structural forms of these proteins showing their structural micro-heterogeneity which is invisible to commonly used immunoassays. These assays are fast, comprehensive and can be applied in large sample studies to analyze proteins for biomarker discovery.
ContributorsRai, Samita (Author) / Nelson, Randall (Thesis advisor) / Hayes, Mark (Thesis advisor) / Borges, Chad (Committee member) / Ros, Alexandra (Committee member) / Arizona State University (Publisher)
Created2012
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Description

Objectives: We estimated neighborhood effects of population characteristics and built and natural environments on deaths due to heat exposure in Maricopa County, Arizona (2000–2008).

Methods: We used 2000 U.S. Census data and remotely sensed vegetation and land surface temperature to construct indicators of neighborhood vulnerability and a geographic information system to

Objectives: We estimated neighborhood effects of population characteristics and built and natural environments on deaths due to heat exposure in Maricopa County, Arizona (2000–2008).

Methods: We used 2000 U.S. Census data and remotely sensed vegetation and land surface temperature to construct indicators of neighborhood vulnerability and a geographic information system to map vulnerability and residential addresses of persons who died from heat exposure in 2,081 census block groups. Binary logistic regression and spatial analysis were used to associate deaths with neighborhoods.

Results: Neighborhood scores on three factors—socioeconomic vulnerability, elderly/isolation, and unvegetated area—varied widely throughout the study area. The preferred model (based on fit and parsimony) for predicting the odds of one or more deaths from heat exposure within a census block group included the first two factors and surface temperature in residential neighborhoods, holding population size constant. Spatial analysis identified clusters of neighborhoods with the highest heat vulnerability scores. A large proportion of deaths occurred among people, including homeless persons, who lived in the inner cores of the largest cities and along an industrial corridor.

Conclusions: Place-based indicators of vulnerability complement analyses of person-level heat risk factors. Surface temperature might be used in Maricopa County to identify the most heat-vulnerable neighborhoods, but more attention to the socioecological complexities of climate adaptation is needed.

ContributorsHarlan, Sharon L. (Author) / Declet-Barreto, Juan H. (Author) / Stefanov, William L. (Author) / Petitti, Diana B. (Author)
Created2013-02-01
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Description

In this study we characterized the relationship between temperature and mortality in central Arizona desert cities that have an extremely hot climate. Relationships between daily maximum apparent temperature (ATmax) and mortality for eight condition-specific causes and all-cause deaths were modeled for all residents and separately for males and females ages

In this study we characterized the relationship between temperature and mortality in central Arizona desert cities that have an extremely hot climate. Relationships between daily maximum apparent temperature (ATmax) and mortality for eight condition-specific causes and all-cause deaths were modeled for all residents and separately for males and females ages <65 and ≥65 during the months May–October for years 2000–2008. The most robust relationship was between ATmax on day of death and mortality from direct exposure to high environmental heat. For this condition-specific cause of death, the heat thresholds in all gender and age groups (ATmax = 90–97 °F; 32.2‒36.1 °C) were below local median seasonal temperatures in the study period (ATmax = 99.5 °F; 37.5 °C). Heat threshold was defined as ATmax at which the mortality ratio begins an exponential upward trend. Thresholds were identified in younger and older females for cardiac disease/stroke mortality (ATmax = 106 and 108 °F; 41.1 and 42.2 °C) with a one-day lag. Thresholds were also identified for mortality from respiratory diseases in older people (ATmax = 109 °F; 42.8 °C) and for all-cause mortality in females (ATmax = 107 °F; 41.7 °C) and males <65 years (ATmax = 102 °F; 38.9 °C). Heat-related mortality in a region that has already made some adaptations to predictable periods of extremely high temperatures suggests that more extensive and targeted heat-adaptation plans for climate change are needed in cities worldwide.

ContributorsHarlan, Sharon L. (Author) / Chowell, Gerardo (Author) / Yang, Shuo (Author) / Petitti, Diana B. (Author) / Morales Butler, Emmanuel J. (Author) / Ruddell, Benjamin L. (Author) / Ruddell, Darren M. (Author)
Created2014-05-20
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Description

Human exposure to excessively warm weather, especially in cities, is an increasingly important public health problem. This study examined heat-related health inequalities within one city in order to understand the relationships between the microclimates of urban neighborhoods, population characteristics, thermal environments that regulate microclimates, and the resources people possess to

Human exposure to excessively warm weather, especially in cities, is an increasingly important public health problem. This study examined heat-related health inequalities within one city in order to understand the relationships between the microclimates of urban neighborhoods, population characteristics, thermal environments that regulate microclimates, and the resources people possess to cope with climatic conditions. A simulation model was used to estimate an outdoor human thermal comfort index (HTCI) as a function of local climate variables collected in 8 diverse city neighborhoods during the summer of 2003 in Phoenix, USA. HTCI is an indicator of heat stress, a condition that can cause illness and death. There were statistically significant differences in temperatures and HTCI between the neighborhoods during the entire summer, which increased during a heat wave period. Lower socioeconomic and ethnic minority groups were more likely to live in warmer neighborhoods with greater exposure to heat stress. High settlement density, sparse vegetation, and having no open space in the neighborhood were significantly correlated with higher temperatures and HTCI. People in warmer neighborhoods were more vulnerable to heat exposure because they had fewer social and material resources to cope with extreme heat. Urban heat island reduction policies should specifically target vulnerable residential areas and take into account equitable distribution and preservation of environmental resources.

ContributorsHarlan, Sharon L. (Author) / Brazel, Anthony J. (Author) / Prashad, Lela (Author) / Stefanov, William L. (Author) / Larsen, Larissa (Author)
Created2006-09-25
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Description

We conducted microclimate simulations in ENVI-Met 3.1 to evaluate the impact of vegetation in lowering temperatures during an extreme heat event in an urban core neighborhood park in Phoenix, Arizona. We predicted air and surface temperatures under two different vegetation regimes: existing conditions representative of Phoenix urban core neighborhoods, and

We conducted microclimate simulations in ENVI-Met 3.1 to evaluate the impact of vegetation in lowering temperatures during an extreme heat event in an urban core neighborhood park in Phoenix, Arizona. We predicted air and surface temperatures under two different vegetation regimes: existing conditions representative of Phoenix urban core neighborhoods, and a proposed scenario informed by principles of landscape design and architecture and Urban Heat Island mitigation strategies. We found significant potential air and surface temperature reductions between representative and proposed vegetation scenarios:

1. A Park Cool Island effect that extended to non-vegetated surfaces.
2. A net cooling of air underneath or around canopied vegetation ranging from 0.9 °C to 1.9 °C during the warmest time of the day.
3. Potential reductions in surface temperatures from 0.8 °C to 8.4 °C in areas underneath or around vegetation.

ContributorsDeclet-Barreto, Juan (Author) / Brazel, Anthony J. (Author) / Martin, Chris A. (Author) / Chow, Winston, 1951- (Author) / Harlan, Sharon L. (Author)
Created2012-12-21
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Description

Urban ecosystems are subjected to high temperatures—extreme heat events, chronically hot weather, or both—through interactions between local and global climate processes. Urban vegetation may provide a cooling ecosystem service, although many knowledge gaps exist in the biophysical and social dynamics of using this service to reduce climate extremes. To better

Urban ecosystems are subjected to high temperatures—extreme heat events, chronically hot weather, or both—through interactions between local and global climate processes. Urban vegetation may provide a cooling ecosystem service, although many knowledge gaps exist in the biophysical and social dynamics of using this service to reduce climate extremes. To better understand patterns of urban vegetated cooling, the potential water requirements to supply these services, and differential access to these services between residential neighborhoods, we evaluated three decades (1970–2000) of land surface characteristics and residential segregation by income in the Phoenix, Arizona, USA metropolitan region. We developed an ecosystem service trade‐offs approach to assess the urban heat riskscape, defined as the spatial variation in risk exposure and potential human vulnerability to extreme heat. In this region, vegetation provided nearly a 25°C surface cooling compared to bare soil on low‐humidity summer days; the magnitude of this service was strongly coupled to air temperature and vapor pressure deficits.

To estimate the water loss associated with land‐surface cooling, we applied a surface energy balance model. Our initial estimates suggest 2.7 mm/d of water may be used in supplying cooling ecosystem services in the Phoenix region on a summer day. The availability and corresponding resource use requirements of these ecosystem services had a strongly positive relationship with neighborhood income in the year 2000. However, economic stratification in access to services is a recent development: no vegetation–income relationship was observed in 1970, and a clear trend of increasing correlation was evident through 2000. To alleviate neighborhood inequality in risks from extreme heat through increased vegetation and evaporative cooling, large increases in regional water use would be required. Together, these results suggest the need for a systems evaluation of the benefits, costs, spatial structure, and temporal trajectory for the use of ecosystem services to moderate climate extremes. Increasing vegetation is one strategy for moderating regional climate changes in urban areas and simultaneously providing multiple ecosystem services. However, vegetation has economic, water, and social equity implications that vary dramatically across neighborhoods and need to be managed through informed environmental policies.

ContributorsJenerette, G. Darrel (Author) / Harlan, Sharon L. (Author) / Stefanov, William L. (Author) / Martin, Chris A. (Author)
Created2011-10-01
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Description

Context:
With rapidly expanding urban regions, the effects of land cover changes on urban surface temperatures and the consequences of these changes for human health are becoming progressively larger problems.

Objectives:
We investigated residential parcel and neighborhood scale variations in urban land surface temperature, land cover, and residents’ perceptions of landscapes and heat

Context:
With rapidly expanding urban regions, the effects of land cover changes on urban surface temperatures and the consequences of these changes for human health are becoming progressively larger problems.

Objectives:
We investigated residential parcel and neighborhood scale variations in urban land surface temperature, land cover, and residents’ perceptions of landscapes and heat illnesses in the subtropical desert city of Phoenix, AZ USA.

Methods:
We conducted an airborne imaging campaign that acquired high resolution urban land surface temperature data (7 m/pixel) during the day and night. We performed a geographic overlay of these data with high resolution land cover maps, parcel boundaries, neighborhood boundaries, and a household survey.

Results:
Land cover composition, including percentages of vegetated, building, and road areas, and values for NDVI, and albedo, was correlated with residential parcel surface temperatures and the effects differed between day and night. Vegetation was more effective at cooling hotter neighborhoods. We found consistencies between heat risk factors in neighborhood environments and residents’ perceptions of these factors. Symptoms of heat-related illness were correlated with parcel scale surface temperature patterns during the daytime but no corresponding relationship was observed with nighttime surface temperatures.

Conclusions:
Residents’ experiences of heat vulnerability were related to the daytime land surface thermal environment, which is influenced by micro-scale variation in land cover composition. These results provide a first look at parcel-scale causes and consequences of urban surface temperature variation and provide a critically needed perspective on heat vulnerability assessment studies conducted at much coarser scales.

ContributorsJenerette, Darrel G. (Author) / Harlan, Sharon L. (Author) / Buyantuev, Alexander (Author) / Stefanov, William L. (Author) / Declet-Barreto, Juan (Author) / Ruddel, Benjamin L. (Author) / Myint, Soe Win (Author) / Kaplan, Shari (Author) / Li, XiaiXiao (Author)
Created2015-10-19
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Description

This study seeks to determine the role of land architecture—the composition and configuration of land cover—as well as cadastral/demographic/economic factors on land surface temperature (LST) and the surface urban heat island effect of Phoenix, Arizona. It employs 1 m National Agricultural Imagery Program data of land-cover with 120mLandsat-derived land surface

This study seeks to determine the role of land architecture—the composition and configuration of land cover—as well as cadastral/demographic/economic factors on land surface temperature (LST) and the surface urban heat island effect of Phoenix, Arizona. It employs 1 m National Agricultural Imagery Program data of land-cover with 120mLandsat-derived land surface temperature, decomposed to 30 m, a new measure of configuration, the normalized moment of inertia, and U.S. Census data to address the question for two randomly selected samples comprising 523 and 545 residential neighborhoods (census blocks) in the city. The results indicate that, contrary to most other studies, land configuration has a stronger influence on LST than land composition. In addition, both land configuration and architecture combined with cadastral, demographic, and economic variables, capture a significant amount of explained variance in LST. The results indicate that attention to land architecture in the development of or reshaping of neighborhoods may ameliorate the summer extremes in LST.

ContributorsLi, Xiaoxiao (Author) / Li, Wenwen (Author) / Middel, Ariane (Author) / Harlan, Sharon L. (Author) / Brazel, Anthony J. (Author) / Turner II, B. L. (Author)
Created2015-12-29