Featured Projects

- How'd they do it? Understanding Successful Physical Activity Experiences among Low-Income African American Women

- Biomedical Informatic Analysis of the RNA of Primary Cells and Tumors Generated Arising in Conditional XRCC4 and p53 Deficient Mouse Background

- Robust Taxonomic Development Using 16s rRNA Phyrosequencing Fragments

- Water Quality Monitoring of Milwaukee Beaches for the Milwaukee Health Department (MHD)

- Guiding Warfarin Clinical Trail Design Using Pharmacogenetic Simulations

- Methylmercury Induced Visual and Neurodevelopmental Deficits in Zebrafish: The Role of DNA Methylation in the Transgenerational Inheritance of Disease Phenotypes

- Predicting Clinical Validity of Bladder Cancer Nomograms'

- Anti-Coagulant Pharmacogenetic Clinical Trial Simulations to Predict Improved Patient Outcomes

- Biomedical Informatic Analysis of the RNA of NF1 Associated Malignant Peripheral Nerve Sheath Tumors (MPNST)

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Perinatal Exposure to Hazardous Air Pollutants and Associations with Autism Phenotype

Amy Kalkbrenner, PhD MPH, Heather Volk, PhD, Gayle Windham, PhD, Nora Lee, PhD
Three studies in different populations have suggested that some hazardous air pollutants may be risk factors for autism. Specifically, methylene chloride and some metals and solvents have been implicated. This study will build upon prior research using a large national sample of children with autism and their families, the Autism Genetic ResourceExchange. After obtaining a residential history for children in these families, we will historically reconstruct exposures to over a hundred volatile organic compounds and metals, using acensus-tract based model of the Environmental Protection Agency. Air pollutant concentrations will be evaluated with regard to not only the diagnosis of autism, but the continuous phenotype of autism symptoms.

In Utero and Childhood Tobacco Exposures and Autistic Traits

Amy Kalkbrenner, PhD, MPH, Joe Braun, PhD, Kim Dietrich,PhD, Kimberly Yolton, PhD, John T. Bernert, PhD, and Bruce Lanphear, MD MPH
Studies have yielded inconsistent results about whether maternal cigarette smoking in pregnancy is associated with autism in the child. We will address prior limitations in research on this topic using a normal pregnancy cohort from Cincinnati,Ohio. We will evaluate whether second-handsmoke in pregnancy, maternal smoking in pregnancy, and second-hand exposure to the child after birth, are associated with autistic traits, after adjusting fora comprehensive set of confounders. In this cohort, tobacco exposures were well-characterized with biomarkers and questionnaires, and the full spectrum of autistic-like behaviors and related social and communication impairments at ages 4 and 5 years was measured using standardized psychometric tools.

Air Pollutants and Autism: New Pathways in Analysis of Windows of Susceptibility

Amy Kalkbrenner, PhD, MPH, Marc Serre, PhD, Gayle Windham,PhD, MSPH, Xuexia Wang, PhD, and Julie Daniels, PhD MPH
Environmental chemical exposures are suspected to contribute to autism, and one study has shown that living closer to freeways is associated with increasing autism risk. We will further understanding in this area by examining the association between 3traffic-related pollutants – course particulate matter, nitrogen dioxide, and ozone – with autism. This case-cohort design includes hundreds of children recognized to have autism in California and North Carolina by the autism surveillance program of the Centers for Disease Control and Prevention, combined with birth records representing the source population and air monitoring data. Notably, we will explore critical windows of susceptibility – exploring whether air pollutant exposures in early pregnancy, late pregnancy, or early childhood are more impactful.

Repeat STI Patients: Tailored Socio-Contextual Intervention to Reduce HIV Risk [pdf]
Lance Weinhardt, PhD, Principal Investigator
Sexually transmitted infections (STI) continue to be a major preventable cause of morbidity in the United States. Some people who are repeatedly infected, defined as people who acquire more than once nonviral STI in 1-2 years, appear to play a key role in sustaining the transmission of STIs in a community. Despite their heightened risk for health complications from STIs, their role in continuing STI transmission, and their heightened risk for HIV infection, there is an absence of empirical research on strategies to intervene with people with repeat STIs. The repeat STI project will fill the gap by developing and evaluating a novel, cost effective, risk reduction intervention.

Pathways Linking Poverty, Food Security, and HIV in Rural Malawi [pdf]

Lance Weinhardt, PhD, Loren Galvao, MD, MPH, Winford Masanjala, PhD, Patricia Stevens, PhD
Poverty and lack of predictable, stable source of food are two fundamental determinants of ill health, including HIV/AIDS. Conversely, episodes of poor health from HIV can disrupt the ability to maintain economic stability in affected households. Research examining how improvements in peoples’ economic status and food security translate into change in HIV vulnerability is lacking. This is particularly germane in the Republic of Malawi, a largely agrarian society, facing severe health vulnerabilities due to poverty, food shortages and high levels of HIV infection. The Pathways project aims to answer the question: “What role does economic change have on HIV-related risk and prevention behaviors and their distribution in a population?”

Developing a Men's Wellness Network to Improve Community Health Outcomes [pdf]

Amy Harley, PhD, MPH, RD, David Frazer, MPH, Jessie Tobin, MPH, Maanaan Sabir, BA, Sharon Adams, Shanee Jenkins
The Lindsay Heights Neighborhood, home to the Lindsay Heights Neighborhood Health Alliance, is abundant with talents and assets, but also faces numerous socio-economic and health challenges. African American men, in particular, bear the burden of stunning disparities in social determinants of health (high rates of unemployment, incarceration, and racism) and health outcomes, including the highest mortality rates in the country. The Health Alliance has identified a need to strengthen the African American male leadership in this neighborhood’s community-wide health promotion and disease prevention efforts.

What's On Your Cereal Box? [pdf]

Bonnie Halvorsen, MA, Hayeon Song, PhD, Amy Harley, PhD, MPH, RD, Lora Jorgensen, MS
This study provides insight into cereal box messages that persuade consumers to buy nutritionally poor foods. It will inform interventions such as social marketing campaigns that help consumers of child-targeting cereals think critically about messages before buying products that are unhealthy for this vulnerable population.

Public Will Building to Reduce Obesity in the Latino Community of Milwaukee [pdf]

Raisa Koltun, Ana Paula Sores, Stephanie Calloway, Amy Harley, PhD, MPH, RD, Loren Galvão, MD, MPH, Samuel Dennis, PhD, Suzanne Galoucher, MPH, MA
Proyecto Salud recognizes that the problem of obesity in the Latino community is equally as detrimental as the lack of engagement in the social change process. With the ultimate goal of reducing obesity in the Milwaukee Latino community, Proyecto Salud proposes taking a public will building approach to address this issue. Public will building is grounded in the philosophy of connecting a community to an issue through its existing values, essentially building public support for social change by understanding existing values and recognizing the context in which we live, work and play.

Evaluation of the Fondy Food Center Youth Chef Academy [pdf]

Amy Harley, PhD, MPH, RD, Young Kim, Lisa Kingery, MS, RD, Lora Jorgensen
The Youth Chef Academy aims to impart skills and knowledge that connect young people to healthy foods, empowering them with culinary skills to prepare healthy, tasty plant based meals and the context to appreciate their role in the local food system that produces and delivers food to them. The Fondy Food Center was interested in working with an academic partner to test the feasibility of conducting the Youth Chef Academy in a classroom setting, and to design an evaluation of its effectiveness in achieving its goals. The evaluation plan includes parent surveys, pre- and post- student surveys, observations of students’ willingness to try new foods and cooking skills, and a brief parent phone interview at completion of the curriculum. Data will be analyzed by observing changes in scores from pre- and post-surveys and qualitatively based on observations made by project staff.

The Young Parenthood Study [pdf]

Paul Florsheim, Ph.D., Sheri Johnson, Ph.D., Trina Salm Ward, M.S.W., C.C.R.C., Megan Howard, M.A., Amy Kirby, M.S.W., L.C.S.W., Laura Ramos, B.A.
The goal of the Milwaukee Young Parenthood Study is to test the efficacy of the Young Parenthood Program (YPP), which is co-parenting counseling program designed to help pregnant adolescents and their biological fathers develop the interpersonal skills needed to provide their child with a safe, secure environment. YPP goals are as follows: (a) increase positive paternal involvement, (b) prevent intimate partner violence and child abuse, (c) reduce rapid repeat pregnancies, (d) reduce maternal stress and (e) support school completion.

How'd they do it? Understanding Successful Physical Activity Experiences among Low-Income African American Women [pdf]

Amy Harley, PhD, MPH, RD, Gary Bennett, PhD , Angela Odoms-Young, PhD, Jessica Rice, MPH
Examining the process by which low-income African American women integrate long-term physical activity (PA) participation into daily life, including examining the role of social and cultural contexts for physical activity participation among low-income African American women.

Biomedical Informatic Analysis of the RNA of Primary Cells and Tumors Generated Arising in Conditional XRCC4 and p53 Deficient Mouse Background

Charles Murphy, Erik Gafni, Parameswary Muniandy, PhD, Himanshu Sharma, Peter J Tonellato, PhD, Catherine Yan, PhD
Combined inactivation of p53 and LIG4, or the LIg4 protein-interactor XRCC4, leads to cancer development in mice in virtually every mouse cell type we have tested. Besides studying the fundamental role of NHEJ proteins in hematopoietic stem cell and the immune system, we have developed several mouse models of human cancers based on conditional inactiviation of the non-homologous end-joining NHEH DNA repair gene XRCC4 and p53. We hypothesize that in addition to known mutations, unknown "driver" mutations cooperate with DNA damage response (DDR) to promote the pathogenesis of the cancers that develop in our models. To test this hypothesis, we will use next generation sequencing and microarray technology to identify mutations (point mutations, small indels, fusion events) and alterations in expression in the transcriptome of the primary mouse cells of origin and cancers. We will perform miRNome and LincRNome analysis to investigate non-coding-mRNA regulations, which we anticipate will serve to identify common and tumor cell type specific driver mutations. We anticipate comparative analysis of the identified mutations to human datasets will identify new, unknown human driver mutations.

Robust Taxanomic development using 16s rRNA Pyrosequencing Fragments

Charles J Murphy, Ryan Newton, PhD, Sandra McLellan, PhD, Peter Tonallato, PhD
Next generation sequencing technology, such as pyrosequencing, can generate large sequence datasets to estimate bacterial communities in biological samples. Pyrosequencing often uses specific genomic regions, such as the 16s rRAN gene, as a stable taxonomic markers. The primary analysis is to estimate bacterial communities in pooled biological samples, but is complicated with the consideration of variable length sequence reads, which poses the technical problem of correlating taxonomies between older technology data (shorter sequence reads) and newer technology data (longer sequence reads); where longer sequences and shorter sequences have overlapping regions. Methods to correlate bacterial communities between longer and shorter sequences are actively being addressed. Presented here is the Hybrid Analysis (HA) that estimates bacterial communities in pooled samples containing variable length sequencing fragments. Initial testing of the HA algorithm are promising; further testing is required.

Water Quality Monitoring of Milwaukee beaches for the Milwaukee Health Department (MHD)

John Hernandez, Chelsea Weirich, Todd Miller, PhD, Rui Du, Aurash Mohaimani, Peter Tonellato, PhD
Bacterial levels of Escherichia coli are the major determinant in closing public beaches; the decision to close beaches is a significant public health concern for the Milwaukee Health Department (MHD). Lake Michigan water samples were collected from three beach sites (Bradford, McKinley, and South Shore) on 63 days spanning the period from early June until late August of 2012. These water samples were assessed for E. coli levels by the University of Wisconsin at Milwaukee (UWM) and MHD; fecal coliform levels in the samples were also investigated by UWM. Environmental conditions, including weather, rainfall, algae content, litter, and wildlife were recorded for each beach on every date. Data has undergone extensive quality assurance, integration, and preliminary analysis. Future work aims to translate and load the data into a database for long-tern storage, extensive analysis, and prediction forecasting. Further work will automate data integration, translation, and loading; a web network and interface will be constructed to provide access to elements from the database and forecasting framework.

Guiding Warfarin Clinical Trial Design using Pharmacogenetic Simulations

Peter J Tonellato PhD, Kourosh Ravvaz, MD, Chun-Yuan Huang, PhD
Highly-sensitive genetic tests that detect variant alleles combined with increasing genomic knowledge offer physicians the ability to individualize a patient’s drug treatment. If pharmacogenomic treatment is successful, one anticipates a large reduction in adverse drug reactions leading to improved patient care, improved outcomes, reduced treatment periods, and overall lower costs. Unfortunately, it is extremely expensive and time-consuming to conduct the clinical trials to identify the correct combination of genotypes, phenotypes, clinical and personal data necessary to accurately model drug response, test treatment options and produce the 'optimal' protocol. In addition, there are no modeling frameworks to extend the simulations and optimization to population wide studies capable of guiding public health policy. Here, we propose the extension and confirmation of a clinical trial simulation framework to model warfarin dosing and INR response to guide clinical trial design. And we ultimately extend the modeling and simulations to city and county-wide predictions which provides evidence to guide public health policy and help direct limited public health resources to avoid health disparity.

Methylmercury Induced Visual and Neurodevelopmental Deficits in Zebrafish: The Role of DNA Methylation in the Transgenerational Inheritence of Disease Phenotypes

Thomas Achankunju, Michael J Carvan, PhD, Peter J Tonellato, PhD
Developmental exposure to environmental pollutants such as pesticides, bisphenol A, dioxin and hydrocarbon compounds have been associated with the onset of adult diseases and transgenerational inheritance of the diseases. Our preliminary studies have identified that developmental exposure to MeHg is correlated to reduced visual startle reflex and altered the response of potassium ion channels of the bipolar cells of the retina in zebrafish. In addition, in our preliminary studies, we have demonstrated that the third generation of fish population also showed altered visual response and retinal electrophysiology as that of the first generation. The third generation is the first generation that was not directly exposed to MeHg but inherited the altered physiology from the MeHg exposed first generation. This is the first evidence of transgenerational inheritance of a phenotype due to developmental exposure to MeHg in any species. The transgenerational effect of MeHg has not been well identified in zebrafish model. The alteration of gene expressions involved in vision and molecular mechanisms behind the transgenerational inheritance of visual defects due to developmental exposure to MeHg are unknown. No studies have been conducted to identify the molecular mechanism of transgenerational inheritance of visual defects induced by MeHg exposure. In our study, we are investigating the gene functions altered in the third generation due to developmental exposure to MeHg in the first generation. The role of DNA methylation, an epigenetic change, in the inheritance will also be investigated in this study.

Predicting Clinical Validity of Bladder Cancer Nomograms

Kourosh Ravvaz, MD, Tracy M Downs, MD, Peter J Tonellato
Complex early stage bladder cancer has growing impact on individual and population health, health care cost, and medical treatment improvements. Bladder cancer is a heterogeneous disease requiring accurately risk group stratification to precisely predict tumor progression and recurrence and therefore accurately treat even early detected, high-risk patients using intravesical therapy. However, current knowledge of risk and treatment is not fully incorporated into commonly used nomograms. This retrospective study being conducted by a multidisciplinary group of researchers from UWM and UW-Madison Carbone Cancer Center will create a simulation framework to test and adjust existing nomograms to include recent clinical findings to produce “optimal” predictions of risk and outcomes.

Anti-Coagulate Pharmacogenetic Clinical Trial Simulations to Predict Improved Patient Outcomes

Peter J Tonellato, PhD, Kourosh Ravvaz, MD, Chun-Yuan Huang, PhD, Michael Michalkiewicz, DVM, PhD Genotype-specific treatments require a large collection of complex clinical trials to identify the combination of genotypes, phenotypes, and clinical data needed to accurately test and identify optimal treatment options in large racially heterogeneous populations. However, these clinical trials are prohibitively expensive. A mathematical modeling approach was previously designed by Prof. Tonellato's group to simulate and predict trial outcomes with the intent to reduce the number, cost and complexity of the trials. In this project, a multidisciplinary research team has joined together to refine and test the model using Aurora Healthcare’s regional patient population EMR data to conduct a series of racially diverse population wide simulations to demonstrate the use of mathematical models and predictive simulation to improve warfarin dosing in a large heterogeneous patient population and provide evidence guiding "optimal" warfarin management policy. Finally, the clinical trial simulation framework will be extended and simulations conducted to predict city, county and regional population outcomes with the aim to produce evidence suggesting how city, county or regional public health care policy may take into consideration genetic testing to guide improved healthcare.

Biomedical Informatic Analysis of the RNA of NF1 Associated Malignant Peripheral Nerve Sheath Tumors (MPNST)

Chun-Yuan Huang, PhD, Chih-Lin Chi, PhD, Charles Joseph Murphy, Rui Du, Kourosh Ravvaz, MD, Zhengqiu Cai, PhD, Erik S. Gafni, Peter J Tonellato, PhD, Steven L Carroll, PhD This research project is conducted by a group of researchers from Dr. Tonellato's laboratories at UWM Zilber School of Public Health (LPHIG) and Harvard Medical School (LPM) and also our collaborators at University of Alabama at Birmingham, Alabama. Patients with neurofibromatosis type 1 (NF1) develop plexiform and intraneural neurofibromas, which in turn transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs). The genetic abnormalities promoting the initial pathogenesis of neurofibromas and their progression to MPNSTs is poorly understood. Although predicted clinically, molecular subtypes of these tumors have not yet been defined. Accurate tumor subtyping is required to rationally design new targeted therapies and define patient subclasses with differing prognoses and responses to specific therapies. We hypothesize that additional, as yet unknown, "driver" mutations cooperate with NF1 loss of heterozygosity to promote the pathogenesis of plexiform and intraneural neurofibromas and MPNSTs. To test this hypothesis, we will use NextGen sequencing to identify mutations (point mutations, small indels, fusion events) and alterations in expression in the transcriptome and/or exosome of human plexiform and intraneural neurofibromas and MPNSTs. We will identify neurofibroma-and MPNST-specific mutations by verifying that candidate mutations are absent in the transcriptomes of normal sciatic nerve and traumatic neuromas, SNP databases and published human genomes. Our long-term objective is thus to comprehensively analyze the genetic abnormalities promoting neurofibroma and MPNST pathogenesis, define molecular subtypes of these tumors and use this information to identify candidate therapeutic targets in each tumor subtype.

University of Wisconsin-Milwaukee

School of Public Health