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Papers by Sarah Knox

$Research paper thumbnail of From \u27omics\u27 to complex disease: a systems biology approach to gene-environment interactions in cancer$

Background Cancer is a complex disease that involves a sequence of gene-environment interactions ... more Background Cancer is a complex disease that involves a sequence of gene-environment interactions in a progressive process that cannot occur without dysfunction in multiple systems, including DNA repair, apoptotic and immune functions. Epigenetic mechanisms, responding to numerous internal and external cues in a dynamic ongoing exchange, play a key role in mediating environmental influences on gene expression and tumor development. Hypothesis The hypothesis put forth in this paper addresses the limited success of treatment outcomes in clinical oncology. It states that improvement in treatment efficacy requires a new paradigm that focuses on reversing systemic dysfunction and tailoring treatments to specific stages in the process. It requires moving from a reductionist framework of seeking to destroy aberrant cells and pathways to a transdisciplinary systems biology approach aimed at reversing multiple levels of dysfunction. Conclusion Because there are many biological pathways and mu...

PLOS ONE, 2018

Background Perfluoroalkyl substances (PFASs) have been associated with decreased immunity to chil... more Background Perfluoroalkyl substances (PFASs) have been associated with decreased immunity to childhood tetanus and diphtheria immunizations. If these vaccinations are vulnerable to influence from PFASs, questions arise about associations with other common inoculations. Objective To examine whether serum PFASs were associated with reduced immunity to rubella immunization, and whether interactions with sex or ethnicity warranted analytic stratification. Usually, toxicology analyses are calculated controlling for race and sex. However, sex differences in immune function have been reported and a reduction of immunity to rubella in women could pose risks such miscarriage. Methods We analyzed a nationally representative sample of individuals ! 12 years from the National Health and Nutrition Examination Survey (NHANES) for years 1999-2000 and 2003-2004 for whom PFAS measures were available. Our analytic strategy was to start with separate analyses for youth and adults controlling for several covariates including ethnicity and sex, as well as the interaction of these terms with PFASs. If there was a main effect of PFASs and an interaction term, we would stratify analyses of effect size. The outcome variable was Rubella IgG titers by quartile of perfluoroalkyl substances. Results After exclusion for missing data, the analyzed sample contained 581 adult women, 621 adult men, and 1012 youth. There was no significant effect of PFASs on immunity in youths but a significant effect of both PFOA and PFOS in adults, as well as a significant interaction of PFOA x sex and a borderline significant interaction of PFOS x sex. When effect size analyses were stratified by sex, a significant association between rubella titres and PFOA was found in men but not women and PFOS was not significant in either sex.

Molecular Biology, 2018

Scientific literature that directly addresses the underlying framework or paradigm of biomedical ... more Scientific literature that directly addresses the underlying framework or paradigm of biomedical research is sparse. We consider ourselves objective scientists in well-defined scientific disciplines and design our studies based on state-of-the-art evidence in our respective fields. However, there is a pervasive underlying assumption that remains unexamined, and in this author's view scientifically unjustified. It is the assumption that because medical conditions occur in the physical body, their causality must be traceable to some form of particulate matter. Although this unspoken assumption is axiomatic in current research, it lacks supporting data. The thesis of this paper is that our assumptions about the underlying nature of reality are outdated with respect to modern physics. Because these assumptions serve as the basis for our study designs, i.e., determine the methodology as well as the variables we include and ignore, inaccurate assumptions risk excluding important data and biasing conclusions. Evidence based medicine is only as good as the research designs on which the evidence is based. If data are lacking because a question, or part of the data related to the question, have been ignored, then the 'evidence' is incomplete. What is missing in mainstream biomedical research, particularly in cancer, is the important role played by endogenously generated bioelectric fields in molecular, cellular and systemic signal processing.

AIMS Molecular Science, 2015

The etiology and progression of the chronic diseases that account for the highest rates of mortal... more The etiology and progression of the chronic diseases that account for the highest rates of mortality in the US, namely, cardiovascular diseases and cancers, involve complex gene x environment interactions. Yet despite the general agreement in the medical community given to this concept, there is a widespread lack of clarity as to what the term 'interaction' actually means. The consequence is the use of linear statistical methods to describe processes that are biologically nonlinear, resulting in clinical applications that are often not optimal. Gene x environment interactions are characterized by dynamic, nonlinear molecular networks that change and evolve over time; and by emergent properties that cannot be deduced from the characteristics of their individual subcomponents. Given the nature of these systemic properties, reductionist methods are insufficient for fully providing the information relevant to improving therapeutic outcomes. The purpose of this article is to provide an overview of these concepts and their relevance to prevention and interventions.

International journal of emergency mental health, 2011

The purpose of this study was to examine the association of police officer stress with metabolic ... more The purpose of this study was to examine the association of police officer stress with metabolic syndrome (MetSyn) and its individual components. Participants included 288 men and 102 women from the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) Study. Police stress was measured using the Spielberger police stress survey. MetSyn was defined using 2005 guidelines. Results were stratified by gender ANCOVA was used to describe differences in number of MetSyn components across police stress categories after adjusting for age and smoking status. Logistic regression was used to calculate odds ratios for having each MetSyn component by increased police stress levels. The multivariate-adjusted number of MetSyn components increased significantly in women across tertiles of the three perceived stress subscales, and administrative and organizational pressure and lack of support indices for the previous month. No association was found among male officers. Abdominal obesity and redu...

The Journal of Toxicological Sciences, 2011

Perfluorocarbons from common household products such as food containers, stainresistant protectio... more Perfluorocarbons from common household products such as food containers, stainresistant protection for clothing, furniture and carpets, paints, and fire-fighting foams are found in soil, water, plants, animal and human serum worldwide. Previous research has shown a significant association between these chemicals and thyroid disease in women. The present data from the C8 Health Project assessed thyroid function in a cross-sectional analysis of 52,296 adults with a year or more of exposure to perfluorooctanoate (PFOA) from drinking water. Outcomes were: thyroxine, T3 uptake, and thyroid stimulating hormone (TSH). Analyses were stratified by gender and age group (< 20-< 50 years and > 50). Both PFOA and perfluorooctane sulfonate (PFOS) were associated with significant elevations in serum thyroxine and a significant reduction in T3 uptake in all participants. There were also significant gender/PFOS interactions for T3 uptake and thyroxine, as well as gender/PFOA interactions for T3 uptake. Results provide evidence for disruption of thyroid function related to these common chemicals and possible mechanisms are discussed.

Scandinavian Journal of Work, Environment & Health, 1984

On the interplay between socioeconomic factors, personality and work environment in the pathogene... more On the interplay between socioeconomic factors, personality and work environment in the pathogenesis of cardiovascular disease. Scand J Work Environ Health 10 (1984) 373-380. This article summarizes some of the major findings in research on associations between psychosocial factors and cardiovascular illness. Methodological difficulties are discussed. Findings from some of the authors' own studies serve as illustrations. It is emphasized that an interplay between environmental and individual factors is of great importance. Personality factors relevant to the risk of cardiovascular illness may distort individual descriptions of the work environment. Cardiovascular risk factors such as cigarette smoking and repeated blood pressure elevations may be influenced by psychosocial factors. Lack of intellectual discretion at work, particularly if combined with excessive demands, may increase the risk of cardiovascular illness.

Psychiatry Research, 2013

We report on the selection of self-report measures for inclusion in the NIH Toolbox that are suit... more We report on the selection of self-report measures for inclusion in the NIH Toolbox that are suitable for assessing the full range of negative affect including sadness, fear, and anger. The Toolbox is intended to serve as a "core battery" of assessment tools for cognition, sensation, motor function, and emotional health that will help to overcome the lack of consistency in measures used across epidemiological, observational, and intervention studies. A secondary goal of the NIH Toolbox is the identification of measures that are flexible, efficient, and precise, an agenda best fulfilled by the use of item banks calibrated with models from item response theory (IRT) and suitable for adaptive testing. Results from a sample of 1,763 respondents supported use of the adult and pediatric item banks for emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS®) as a starting point for capturing the full range of negative affect in healthy individuals. Content coverage for the adult Toolbox was also enhanced by the development of a scale for somatic arousal using items from the Mood and Anxiety Symptom Questionnaire (MASQ) and scales for hostility and physical aggression using items from the Buss-Perry Aggression Questionnaire (BPAQ).

PLoS ONE, 2010

Background: Both anxiety and elevated heart rate (HR) have been implicated in the development of ... more Background: Both anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N = 1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups. Methodology: The interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style).

Neurology, 2013

One of the goals of the NIH Toolbox for Assessment of Neurological and Behavioral Function was to... more One of the goals of the NIH Toolbox for Assessment of Neurological and Behavioral Function was to identify or develop brief measures of emotion for use in prospective epidemiologic and clinical research. Emotional health has significant links to physical health and exerts a powerful effect on perceptions of life quality. Based on an extensive literature review and expert input, the Emotion team identified 4 central subdomains: Negative Affect, Psychological Well-Being, Stress and Self-Efficacy, and Social Relationships. A subsequent psychometric review identified several existing self-report and proxy measures of these subdomains with measurement characteristics that met the NIH Toolbox criteria. In cases where adequate measures did not exist, robust item banks were developed to assess concepts of interest. A population-weighted sample was recruited by an online survey panel to provide initial item calibration and measure validation data. Participants aged 8 to 85 years completed self-report measures whereas parents/guardians responded for children aged 3 to 12 years. Data were analyzed using a combination of classic test theory and item response theory methods, yielding efficient measures of emotional health concepts. An overview of the development of the NIH Toolbox Emotion battery is presented along with preliminary results. Norming activities led to further refinement of the battery, thus enhancing the robustness of emotional health measurement for researchers using the NIH Toolbox. Neurology â 2013;80 (Suppl 3):S76-S86 GLOSSARY IRT 5 item response theory; NA 5 negative affect; PROMIS 5 Patient Reported Outcomes Measurement Information System; RFI 5 Request for Information. In everyday terms, the word "emotion" evokes connotations of strong feelings, often negative and distressing when they tax our capacity to maintain our poise. It is unpleasant when we are extended beyond our usual resources by stressful life events including poverty, unemployment, oppression, discrimination, and disease. However, positive emotions can be reflections of well-being in our lives, and positive social relationships can buffer stress and enhance health. Recognizing the full spectrum of emotional life and its impact on health, the mandate for the NIH Toolbox was to develop assessments with a broad focus, beyond just negative emotion, or emotional distress. The original Request for Proposals alluded to several additional aspects of the experience and expression of emotion relevant to health in the general population including the importance of psychological well-being, the role of important aspects of positive functioning, such as adaptability, resilience, and self-efficacy, and the importance of the interpersonal and social context in which emotions arise and may be expressed. Feedback provided through an NIH Toolbox Expert Request for Information (RFI) was also consistent with this desire for a broad emphasis on emotional health. As part of this RFI, we obtained input from 147 experts (64% of 232 invited experts), including key opinion leaders from the NIH research program staff and NIH-funded investigators with a broad focus in neurologic and behavioral

Molecular Psychiatry, 2003

Journal of Epidemiology & Community Health, 2009

This paper provides a strategy for the assessment of brain function in longitudinal cohort studie... more This paper provides a strategy for the assessment of brain function in longitudinal cohort studies of children. The proposed strategy invokes both domain-specific and omnibus intelligence test approaches. In order to minimise testing burden and practice effects, the cohort is divided into four groups with one-quarter tested at 6-monthly intervals in the 0-2-year age range (at ages 6 months, 1.0, 1.5 and 2.0 years) and at annual intervals from ages 3-20 (one-quarter of the children at age 3, another at age 4, etc). This strategy allows investigation of cognitive development and of the relationship between environmental influences and development at each age. It also allows introduction of new domains of function when age-appropriate. As far as possible, tests are used that will provide a rich source of both longitudinal and cross-sectional data. The testing strategy allows the introduction of novel tests and new domains as well as piloting of tests when the test burden is relatively light. In addition to the recommended tests for each age and domain, alternative tests are described. Assessment methodology and knowledge about child cognitive development will change over the next 20 years, and strategies are suggested for altering the proposed test schedule as appropriate. DOMAINS OF RESEARCH INTEREST Categorising the dimensions of cognition into component parts is challenging even to cognitive psychologists and neuropsychologists, who often divide or subdivide these dimensions in different ways. It is even more difficult to categorise existing cognitive and behavioural tests since few were designed to be pure tests of a specific aspect of cognitive processing or a single domain. For the purposes of developing a recommended battery, domains were identified using the labels commonly applied in clinical neuropsychology. 3 4 In addition, careful consideration was given to key aspects of processing that should be assessed within each domain. The following list identifies the domains selected by the authors and associated defining characteristics. The definitions are not meant to be exhaustive but to give the reader an overview of the types of skills subsumed under each domain and assessed by associated neuropsychological tasks. General intelligence/mental abilities/omnibus cognitive skills tests These tests consist of subtests with various labels purported to measure aspects of cognitive function.

The Journal of Clinical Endocrinology & Metabolism, 2011

Context: Perfluorocarbons (PFC) are man-made chemicals used in numerous household products. They ... more Context: Perfluorocarbons (PFC) are man-made chemicals used in numerous household products. They have a long half-life in humans and complex animal toxicity, and accumulating evidence points toward associations with multiple human health endpoints. Objective: Our objective was to investigate whether PFC are associated with endocrine disruption in women. Design: Cross-sectional analyses were made between quintiles of serum PFC, serum estradiol, and menopause onset. Setting: The C8 Health Project, with cohort of 69,030 adults and children, was conducted due to PFC contamination of drinking water from six water districts in two states. Participants: Participants included 25,957 women aged 18-65 yr. Main Outcome Measures: Serum estradiol levels and onset of menopause were assessed. The survey was the result of a class action suit, and survey designers (an independent corporation) had no a priori hypotheses. All hypotheses have been formulated by other investigators after data collection. Results: After excluding women who reported hysterectomy and adjusting for age within the group, smoking, alcohol consumption, body mass index, and exercise, the odds of having experienced menopause were significantly higher in the highest quintile relative to the lowest quintile of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) in the perimenopausal [PFOS odds ϭ 1.4, confidence interval (CI) ϭ 1.1-1.8; PFOA odds ϭ1.4, CI ϭ 1.1-1.8] and menopausal age groups (PFOS odds ϭ 2.1, CIϭ1.6-2.8; PFOA odds ϭ 1.7, CI ϭ 1.3-2.3). After appropriate exclusions and adjustment for covariates, there was a significant inverse association between PFOS and estradiol in perimenopausal (␤ ϭ Ϫ3.65; P Ͻ 0.0001) and menopausal age groups (␤ ϭ Ϫ0.83; P ϭ 0.007) but not between PFOA and estradiol. Conclusions: These data suggest that PFC are associated with endocrine disruption in women and that further research on mechanisms is warranted.

Gene Regulation and Systems Biology, 2013

The current approach to treatment in oncology is to replace the generally cytotoxic chemotherapie... more The current approach to treatment in oncology is to replace the generally cytotoxic chemotherapies with pharmaceutical treatment which inactivates specific molecular targets associated with cancer development and progression. The goal is to limit cellular damage to pathways perceived to be directly responsible for the malignancy. Its underlying assumptions are twofold: (1) that individual pathways are the cause of malignancy; and (2) that the treatment objective should be destruction–-either of the tumor or the dysfunctional pathway. However, the extent to which data actually support these assumptions has not been directly addressed. Accumulating evidence suggests that systemic dysfunction precedes the disruption of specific genetic/molecular pathways in most adult cancers and that targeted treatments such as kinase inhibitors may successfully treat one pathway while generating unintended changes to other, non-targeted pathways. This article discusses (1) the systemic basis of malig...

Environmental Science & Technology, 2013

Perfluoroalkyl substances are manmade chemicals used in many consumer products and have become ub... more Perfluoroalkyl substances are manmade chemicals used in many consumer products and have become ubiquitous in the environment. Animal studies and a limited number of human studies have demonstrated developmental effects in offspring exposed to perfluoroalkyl substances in utero, but the implications of timing of in utero exposure have not been systematically investigated. The present study investigated variation in perfluorocarbon levels of 9952 women of childbearing age who had been exposed to perfluorooctanoic acid (PFOA) in drinking water contaminated by industrial waste. An analysis of variance with contrast was performed to compare the levels of PFOA and perfluorooctanesulfonic acid (PFOS) in pregnant and nonpregnant women overall and during each trimester of pregnancy. We found that pregnant women had lower circulating PFOA and PFOS concentrations in peripheral blood than nonpregnant women and that PFOA levels were consistently lower throughout all trimesters for pregnancy, suggesting transfer to the fetus at an early stage of gestation. These results are discussed in the context of the endocrine-disrupting properties of perfluoroalkyl substances that have been characterized in animal and human studies. Our conclusion is that further, systematic study of the potential implications of intrauterine perfluorocarbon exposure during critical periods of fetal development is urgently needed.

Environmental Health Perspectives, 2009

Circulation, 2012

Background— Because depression is a multidimensional construct and few studies have compared the ... more Background— Because depression is a multidimensional construct and few studies have compared the relative importance of its facets in predicting cardiovascular risk, we evaluated the utility of depressive symptom clusters in predicting the 5-year incidence of coronary artery calcification (CAC). Methods and Results— Participants were 2171 middle-aged adults (58% female; 43% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were free of cardiovascular disease. Depressive symptom clusters ( z scores) were measured by questionnaires in 2000 to 2001, and CAC was measured by electron beam computed tomography in 2000 to 2001 and 2005 to 2006. There were 243 cases (11%) of incident CAC, defined as the absence of CAC at baseline and the presence of CAC at follow-up. Total depressive symptoms (odds ratio, 1.16; 95% confidence interval, 1.02–1.33; P =0.03) and the depressed affect cluster (odds ratio, 1.17; 95% confidence interval, 1.03–1.33; P =0.02) predict...

Cancer Cell International, 2010

Background: Cancer is a complex disease that involves a sequence of gene-environment interactions... more Background: Cancer is a complex disease that involves a sequence of gene-environment interactions in a progressive process that cannot occur without dysfunction in multiple systems, including DNA repair, apoptotic and immune functions. Epigenetic mechanisms, responding to numerous internal and external cues in a dynamic ongoing exchange, play a key role in mediating environmental influences on gene expression and tumor development. Hypothesis: The hypothesis put forth in this paper addresses the limited success of treatment outcomes in clinical oncology. It states that improvement in treatment efficacy requires a new paradigm that focuses on reversing systemic dysfunction and tailoring treatments to specific stages in the process. It requires moving from a reductionist framework of seeking to destroy aberrant cells and pathways to a transdisciplinary systems biology approach aimed at reversing multiple levels of dysfunction. Conclusion: Because there are many biological pathways and multiple epigenetic influences working simultaneously in the expression of cancer phenotypes, studying individual components in isolation does not allow an adequate understanding of phenotypic expression. A systems biology approach using new modeling techniques and nonlinear mathematics is needed to investigate gene-environment interactions and improve treatment efficacy. A broader array of study designs will also be required, including prospective molecular epidemiology, immune competent animal models and in vitro/in vivo translational research that more accurately reflects the complex process of tumor initiation and progression.

Arteriosclerosis, Thrombosis, and Vascular Biology, 2010

Objective— Aberrations in apolipoprotein (apo) metabolism and increased systemic inflammation ass... more Objective— Aberrations in apolipoprotein (apo) metabolism and increased systemic inflammation associate with the metabolic syndrome (MetS) and may contribute to its atherogenicity. We examined whether the association between carotid atherosclerosis and MetS in a population of young adults is mediated by apoB and apoA-I and/or by inflammatory markers C-reactive protein and type II secretory phospholipase A2. Methods and Results— We used cross-sectional and 6-year prospective data from the cardiovascular risk in young Finns study. In young adults (aged 24 to 39 years), apoB, C-reactive protein, and type II secretory phospholipase A2 enzyme activity were significantly higher and apoA-I lower in subjects with MetS (N=325) than in subjects without MetS (N=1858). In prospective analysis (N=1587), both MetS and high apoB predicted ( P <0.0001) incident high carotid intima-media thickness, defined as carotid intima-media thickness >90th percentile and/or plaque. The association betwee...