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1.  Association between Lifetime Exposure to Inorganic Arsenic in Drinking Water and Coronary Heart Disease in Colorado Residents 
Environmental Health Perspectives  2014;123(2):128-134.
Background: Chronic diseases, including coronary heart disease (CHD), have been associated with ingestion of drinking water with high levels of inorganic arsenic (> 1,000 μg/L). However, associations have been inconclusive in populations with lower levels (< 100 μg/L) of inorganic arsenic exposure.
Objectives: We conducted a case-cohort study based on individual estimates of lifetime arsenic exposure to examine the relationship between chronic low-level arsenic exposure and risk of CHD.
Methods: This study included 555 participants with 96 CHD events diagnosed between 1984 and 1998 for which individual lifetime arsenic exposure estimates were determined using data from structured interviews and secondary data sources to determine lifetime residence, which was linked to a geospatial model of arsenic concentrations in drinking water. These lifetime arsenic exposure estimates were correlated with historically collected urinary arsenic concentrations. A Cox proportional-hazards model with time-dependent CHD risk factors was used to assess the association between time-weighted average (TWA) lifetime exposure to low-level inorganic arsenic in drinking water and incident CHD.
Results: We estimated a positive association between low-level inorganic arsenic exposure and CHD risk [hazard ratio (HR): = 1.38, 95% CI: 1.09, 1.78] per 15 μg/L while adjusting for age, sex, first-degree family history of CHD, and serum low-density lipoprotein levels. The risk of CHD increased monotonically with increasing TWAs for inorganic arsenic exposure in water relative to < 20 μg/L (HR = 1.2, 95% CI: 0.6, 2.2 for 20–30 μg/L; HR = 2.2; 95% CI: 1.2, 4.0 for 30–45 μg/L; and HR = 3, 95% CI: 1.1, 9.1 for 45–88 μg/L).
Conclusions: Lifetime exposure to low-level inorganic arsenic in drinking water was associated with increased risk for CHD in this population.
Citation: James KA, Byers T, Hokanson JE, Meliker JR, Zerbe GO, Marshall JA. 2015. Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ Health Perspect 123:128–134; http://dx.doi.org/10.1289/ehp.1307839
doi:10.1289/ehp.1307839
PMCID: PMC4314243  PMID: 25350952
2.  Dignity in end-of-life care: results of a national survey of US physicians 
Context
Debates persist about the relevance of “dignity” as an ethical concept in US healthcare, especially in end-of-life care.
Objective
To describe the attitudes and beliefs regarding the usefulness and meaning of the concept of dignity and to examine judgments about a clinical scenario in which dignity might be relevant.
Methods
2000 practicing U.S. physicians, from all specialties, were mailed a survey. Main measures included physician’s judgments about an end-of-life clinical scenario (criterion variable), attitudes about the concept of dignity (predictors), and their religious characteristics (predictors).
Results
1032 eligible physicians (54%) responded. Nine out of ten (90%) physicians reported that dignity was relevant to their practice. After controlling for age, gender, region, and specialty, physicians who judged that the case patient had either some dignity or full dignity, and who agreed that dignity is given by a creator, were all positively associated with believing that the patient’s life was worth living [OR 10.2 (5.8–17.8), OR 20.5 (11.4–36.8), OR 4.7 (3.1–7.0), respectively]. Respondents who strongly agreed that “all living humans have the same amount of dignity” were also more likely to believe that the patient’s life was worth living [OR 1.8 (1.2–2.7)]. Religious characteristics were also associated with believing that the case patient’s life was worth living [OR 4.1 (2.4–7.2), OR 3.2 (1.6–6.3), OR 9.2 (4.3–19.5), respectively].
Conclusion
US physicians view the concept of dignity as useful. Those views are associated with their judgments about common end-of-life scenarios in which dignity concepts may be relevant.
doi:10.1016/j.jpainsymman.2011.09.020
PMCID: PMC3967404  PMID: 22762966
human dignity; end-of-life care; physician religiosity
3.  Listening in on difficult conversations: an observational, multi-center investigation of real-time conversations in medical oncology 
BMC Cancer  2013;13:455.
Background
The quality of communication in medical care has been shown to influence health outcomes. Cancer patients, a highly diverse population, communicate with their clinical care team in diverse ways over the course of their care trajectory. Whether that communication happens and how effective it is may relate to a variety of factors including the type of cancer and the patient’s position on the cancer care continuum. Yet, many of the routine needs of cancer patients after initial cancer treatment are often not addressed adequately. Our goal is to identify areas of strength and areas for improvement in cancer communication by investigating real-time cancer consultations in a cross section of patient-clinician interactions at diverse study sites.
Methods/design
In this paper we describe the rationale and approach for an ongoing observational study involving three institutions that will utilize quantitative and qualitative methods and employ a short-term longitudinal, prospective follow-up component to investigate decision-making, key topics, and clinician-patient-companion communication dynamics in clinical oncology.
Discussion
Through a comprehensive, real-time approach, we hope to provide the fundamental groundwork from which to promote improved patient-centered communication in cancer care.
doi:10.1186/1471-2407-13-455
PMCID: PMC3850997  PMID: 24093624
Cancer; Oncology; Physician-patient communication
4.  The moral psychology of rationing among physicians: the role of harm and fairness intuitions in physician objections to cost-effectiveness and cost-containment 
Introduction
Physicians vary in their moral judgments about health care costs. Social intuitionism posits that moral judgments arise from gut instincts, called “moral foundations.” The objective of this study was to determine if “harm” and “fairness” intuitions can explain physicians’ judgments about cost-containment in U.S. health care and using cost-effectiveness data in practice, as well as the relative importance of those intuitions compared to “purity”, “authority” and “ingroup” in cost-related judgments.
Methods
We mailed an 8-page survey to a random sample of 2000 practicing U.S. physicians. The survey included the MFQ30 and items assessing agreement/disagreement with cost-containment and degree of objection to using cost-effectiveness data to guide care. We used t-tests for pairwise subscale mean comparisons and logistic regression to assess associations with agreement with cost-containment and objection to using cost-effectiveness analysis to guide care.
Results
1032 of 1895 physicians (54%) responded. Most (67%) supported cost-containment, while 54% expressed a strong or moderate objection to the use of cost-effectiveness data in clinical decisions. Physicians who strongly objected to the use of cost-effectiveness data had similar scores in all five of the foundations (all p-values > 0.05). Agreement with cost-containment was associated with higher mean “harm” (3.6) and “fairness” (3.5) intuitions compared to “in-group” (2.8), “authority” (3.0), and “purity” (2.4) (p < 0.05). In multivariate models adjusted for age, sex, region, and specialty, both “harm” and “fairness” were significantly associated with judgments about cost-containment (OR = 1.2 [1.0-1.5]; OR = 1.7 [1.4-2.1], respectively) but were not associated with degree of objection to cost-effectiveness (OR = 1.2 [1.0-1.4]; OR = 0.9 [0.7-1.0]).
Conclusions
Moral intuitions shed light on variation in physician judgments about cost issues in health care.
doi:10.1186/1747-5341-8-13
PMCID: PMC3847359  PMID: 24010636
Physicians; Survey; Moral beliefs; Cost-effectiveness; Cost-containment
5.  “Righteous Minds” in Health Care: Measurement and Explanatory Value of Social Intuitionism in Accounting for the Moral Judgments in a Sample of U.S. Physicians 
PLoS ONE  2013;8(9):e73379.
The broad diversity in physicians’ judgments on controversial health care topics may reflect differences in religious characteristics, political ideologies, and moral intuitions. We tested an existing measure of moral intuitions in a new population (U.S. physicians) to assess its validity and to determine whether physicians’ moral intuitions correlate with their views on controversial health care topics as well as other known predictors of these intuitions such as political affiliation and religiosity. In 2009, we mailed an 8-page questionnaire to a random sample of 2000 practicing U.S. physicians from all specialties. The survey included the Moral Foundations Questionnaire (MFQ30), along with questions on physicians’ judgments about controversial health care topics including abortion and euthanasia (no moral objection, some moral objection, strong moral objection). A total of 1032 of 1895 (54%) physicians responded. Physicians’ overall mean moral foundations scores were 3.5 for harm, 3.3 for fairness, 2.8 for loyalty, 3.2 for authority, and 2.7 for sanctity on a 0–5 scale. Increasing levels of religious service attendance, having a more conservative political ideology, and higher sanctity scores remained the greatest positive predictors of respondents objecting to abortion (β = 0.12, 0.23, 0.14, respectively, each p<0.001) as well as euthanasia (β = 0.08, 0.17, and 0.17, respectively, each p<0.001), even after adjusting for demographics. Higher authority scores were also significantly negatively associated with objection to abortion (β = −0.12, p<0.01), but not euthanasia. These data suggest that the relative importance physicians place on the different categories of moral intuitions may predict differences in physicians’ judgments about morally controversial topics and may interrelate with ideology and religiosity. Further examination of the diversity in physicians’ moral intuitions may prove illustrative in describing and addressing moral differences that arise in medical practice.
doi:10.1371/journal.pone.0073379
PMCID: PMC3762735  PMID: 24023864
8.  Getting Physicians to Respond: The Impact of Incentive Type and Timing on Physician Survey Response Rates 
Health Services Research  2011;46(1 Pt 1):232-242.
Objective
To study the effects of payment timing, form of payment, and requiring a social security number (SSN) on survey response rates.
Data Source
Third-wave mailing of a U.S. physician survey.
Study Design
Nonrespondents were randomized to receive immediate U.S.$25 cash, immediate U.S.$25 check, promised U.S.$25 check, or promised U.S.$25 check requiring an SSN.
Data Collection Methods
Paper survey responses were double entered into statistical software.
Principal Findings
Response rates differed significantly between remuneration groups (χ32=80.1, p<.0001), with the highest rate in the immediate cash group (34 percent), then immediate check (20 percent), promised check (10 percent), and promised check with SSN (8 percent).
Conclusions
Immediate monetary incentives yield higher response rates than promised in this population of nonresponding physicians. Promised incentives yield similarly low response rates regardless of whether an SSN is requested.
doi:10.1111/j.1475-6773.2010.01181.x
PMCID: PMC3034272  PMID: 20880042
Physicians; surveys; response rate; incentives
9.  How Patients View Probiotics: Findings from a Multicenter Study of Patients with Inflammatory Bowel Disease and Irritable Bowel Syndrome 
Background
Patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) have access to a growing number of probiotic products marketed to improve digestive health. It is unclear how patients make decisions about probiotics and what role they expect their gastroenterologists to play as they consider using probiotics. Understanding patients’ knowledge, attitudes and expectations of probiotics may help gastroenterologists engage patients in collaborative discussions about probiotics.
Study
Focus groups were conducted with patients with IBD and IBS at the Cleveland Clinic, Mayo Clinic and Johns Hopkins University. Inductive analytic methods were utilized to identify common themes and draw interpretations from focus group narratives.
Results
One hundred thirty-six patients participated in 22 focus groups between March and August 2009. Patients viewed probiotics as an appealing alternative to pharmaceutical drugs and understood probiotics as a more “natural,” low-risk therapeutic option. Many patients were hesitant to use them without consulting their gastroenterologists. Patients would weigh the risks and benefits of probiotics, their disease severity and satisfaction with current treatments when considering probiotic use.
Conclusions
Patients are interested in probiotics but have many unanswered questions about their use. Our findings suggest that patients with IBD and IBS will look to gastroenterologists and other clinicians as trustworthy advisors regarding the utility of probiotics as an alternative or supplement to pharmaceutical drugs. Gastroenterologists and other clinicians who care for patients with these diseases should be prepared to discuss the potential benefits and risks of probiotics and assist patients in making informed decisions about their use.
doi:10.1097/MCG.0b013e318225f545
PMCID: PMC3202682  PMID: 21716123
probiotics; patient communication; ethics
10.  Bayesian integration of networks without gold standards 
Bioinformatics  2012;28(11):1495-1500.
Motivation: Biological experiments give insight into networks of processes inside a cell, but are subject to error and uncertainty. However, due to the overlap between the large number of experiments reported in public databases it is possible to assess the chances of individual observations being correct. In order to do so, existing methods rely on high-quality ‘gold standard’ reference networks, but such reference networks are not always available.
Results: We present a novel algorithm for computing the probability of network interactions that operates without gold standard reference data. We show that our algorithm outperforms existing gold standard-based methods. Finally, we apply the new algorithm to a large collection of genetic interaction and protein–protein interaction experiments.
Availability: The integrated dataset and a reference implementation of the algorithm as a plug-in for the Ondex data integration framework are available for download at http://bio-nexus.ncl.ac.uk/projects/nogold/
Contact: darren.wilkinson@ncl.ac.uk
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts154
PMCID: PMC3356839  PMID: 22492647
11.  Impact of Direct-to-Consumer Predictive Genomic Testing on Risk Perception and Worry Among Patients Receiving Routine Care in a Preventive Health Clinic 
Mayo Clinic Proceedings  2011;86(10):933-940.
OBJECTIVE: To assess the impact of direct-to-consumer (DTC) predictive genomic risk information on perceived risk and worry in the context of routine clinical care.
PATIENTS AND METHODS: Patients attending a preventive medicine clinic between June 1 and December 18, 2009, were randomly assigned to receive either genomic risk information from a DTC product plus usual care (n=74) or usual care alone (n=76). At intervals of 1 week and 1 year after their clinic visit, participants completed surveys containing validated measures of risk perception and levels of worry associated with the 12 conditions assessed by the DTC product.
RESULTS: Of 345 patients approached, 150 (43%) agreed to participate, 64 (19%) refused, and 131 (38%) did not respond. Compared with those receiving usual care, participants who received genomic risk information initially rated their risk as higher for 4 conditions (abdominal aneurysm [P=.001], Graves disease [P=.04], obesity [P=.01], and osteoarthritis [P=.04]) and lower for one (prostate cancer [P=.02]). Although differences were not significant, they also reported higher levels of worry for 7 conditions and lower levels for 5 others. At 1 year, there were no significant differences between groups.
CONCLUSION: Predictive genomic risk information modestly influences risk perception and worry. The extent and direction of this influence may depend on the condition being tested and its baseline prominence in preventive health care and may attenuate with time.
Trial Registration: clinicaltrials.gov identifier: NCT00782366
doi:10.4065/mcp.2011.0190
PMCID: PMC3184022  PMID: 21964170
12.  Getting physicians to open the survey: little evidence that an envelope teaser increases response rates 
Background
Physician surveys are an important tool to assess attitudes, beliefs and self-reported behaviors of this policy relevant group. In order for a physician to respond to a mailed survey, they must first open the envelope. While there is some evidence that package elements can impact physician response rates, the impact of an envelope teaser is unknown. Here we assess this by testing the impact of adding a brightly colored "$25 incentive" sticker to the outside of an envelope on response rates and nonresponse bias in a survey of physicians.
Methods
In the second mailing of a survey assessing physicians' moral beliefs and views on controversial health care topics, initial nonrespondents were randomly assigned to receive a survey in an envelope with a colored "$25 incentive" sticker (teaser group) or an envelope without a sticker (control group). Response rates were compared between the teaser and control groups overall and by age, gender, region of the United States, specialty and years in practice. Nonresponse bias was assessed by comparing the demographic composition of the respondents to the nonrespondents in the experimental and control condition.
Results
No significant differences in response rates were observed between the experimental and control conditions overall (p = 0.38) or after stratifying by age, gender, region, or practice type. Within the teaser condition, there was some variation in response rate by years since graduation. There was no independent effect of the teaser on response when simultaneously controlling for demographic characteristics (OR = 0.875, p = 0.4112).
Conclusions
Neither response rates nor nonresponse bias were impacted by the use of an envelope teaser in a survey of physicians in the United States.
doi:10.1186/1471-2288-12-41
PMCID: PMC3350455  PMID: 22463734
Survey methods; Response rates; Physician surveys
13.  Experiences of patients with chronic gastrointestinal conditions: in their own words 
Background
Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are chronic conditions affecting millions of individuals in the United States. The symptoms are well-documented and can be debilitating. How these chronic gastrointestinal (GI) conditions impact the daily lives of those afflicted is not well documented, especially from a patient's perspective.
Methods
Here we describe data from a series of 22 focus groups held at three different academic medical centers with individuals suffering from chronic GI conditions. All focus groups were audio recorded and transcribed. Two research team members independently analyzed transcripts from each focus group following an agreed upon coding scheme.
Results
One-hundred-thirty-six individuals participated in our study, all with a chronic GI related condition. They candidly discussed three broad themes that characterize their daily lives: identification of disease and personal identity, medications and therapeutics, and daily adaptations. These all tie to our participants trying to deal with symptoms on a daily basis. We find that a recurrent topic underlying these themes is the dichotomy of experiencing uncertainty and striving for control.
Conclusions
Study participants' open dialogue and exchange of experiences living with a chronic GI condition provide insight into how these conditions shape day-to-day activities. Our findings provide fertile ground for discussions about how clinicians might best facilitate, acknowledge, and elicit patients' stories in routine care to better address their experience of illness.
doi:10.1186/1477-7525-10-25
PMCID: PMC3349594  PMID: 22401607
Chronic gastrointestinal conditions; Inflammatory Bowel Disease; Irritable Bowel Syndrome; Patient adaptation; Symptom experience
14.  Getting physicians to respond: The impact of incentive type and timing on physician survey response rates 
Health services research  2010;46(1 Pt 1):232-242.
Objective
To study the effects of payment timing, form of payment, and requiring a social security number on survey response rates.
Data Source
Third wave mailing of a U.S. physician survey.
Study Design
Non-respondents were randomized to receive immediate $25 cash, immediate $25 check, promised $25 check, or promised $25 check requiring a SSN.
Data Collection Methods
Paper survey responses were double entered into statistical software.
Principal Findings
Response rates differed significantly between remuneration groups (χ23 = 80.1, p < 0.0001), with the highest rate in the immediate cash group (34%), then immediate check (20%), promised check (10%), and promised check with SSN (8%).
Conclusions
Immediate monetary incentives yield higher response rates than promised in this population of non-responding physicians. Promised incentives yield similarly low response rates whether or not a SSN is requested.
doi:10.1111/j.1475-6773.2010.01181.x
PMCID: PMC3034272  PMID: 20880042
Physicians; surveys; response rate; incentives
16.  Attitudes toward and Uptake of H1N1 Vaccine among Health Care Workers during the 2009 H1N1 Pandemic 
PLoS ONE  2011;6(12):e29478.
Background
Though recommended by many and mandated by some, influenza vaccination rates among health care workers, even in pandemics, remain below optimal levels. The objective of this study was to assess vaccination uptake, attitudes, and distinguishing characteristics (including doctor-nurse differences) of health care workers who did and did not receive the pandemic H1N1 influenza vaccine in late 2009.
Methodology/Principal Findings
In early 2010 we mailed a self-administered survey to 800 physicians and 800 nurses currently licensed and practicing in Minnesota. 1,073 individuals responded (cooperation rate: 69%). 85% and 62% of Minnesota physicians and nurses, respectively, reported being vaccinated. Accurately estimating the risk of vaccine side effects (OR 2.0; 95% CI 1.5–2.7), agreeing with a professional obligation to be vaccinated (OR 10.1; 95% CI 7.1–14.2), an ethical obligation to follow public health authorities' recommendations (OR 9.9; 95% CI 6.6–14.9), and laws mandating pandemic vaccination (OR 3.1; 95% CI 2.3–4.1) were all independently associated with receiving the H1N1 influenza vaccine.
Conclusions/Significance
While a majority of health care workers in one midwestern state reported receiving the pandemic H1N1 vaccine, physicians and nurses differed significantly in vaccination uptake. Several key attitudes and perceptions may influence health care workers' decisions regarding vaccination. These data inform how states might optimally enlist health care workers' support in achieving vaccination goals during a pandemic.
doi:10.1371/journal.pone.0029478
PMCID: PMC3245279  PMID: 22216290
17.  Duty Hour Recommendations and Implications for Meeting the ACGME Core Competencies: Views of Residency Directors 
Mayo Clinic Proceedings  2011;86(3):185-191.
OBJECTIVE: To describe the views of residency program directors regarding the effect of the 2010 duty hour recommendations on the 6 core competencies of graduate medical education.
METHODS: US residency program directors in internal medicine, pediatrics, and general surgery were e-mailed a survey from July 8 through July 20, 2010, after the 2010 Accreditation Council for Graduate Medical Education (ACGME) duty hour recommendations were published. Directors were asked to rate the implications of the new recommendations for the 6 ACGME core competencies as well as for continuity of inpatient care and resident fatigue.
RESULTS: Of 719 eligible program directors, 464 (65%) responded. Most program directors believe that the new ACGME recommendations will decrease residents' continuity with hospitalized patients (404/464 [87%]) and will not change (303/464 [65%]) or will increase (26/464 [6%]) resident fatigue. Additionally, most program directors (249-363/464 [53%-78%]) believe that the new duty hour restrictions will decrease residents' ability to develop competency in 5 of the 6 core areas. Surgery directors were more likely than internal medicine directors to believe that the ACGME recommendations will decrease residents' competency in patient care (odds ratio [OR], 3.9; 95% confidence interval [CI], 2.5-6.3), medical knowledge (OR, 1.9; 95% CI, 1.2-3.2), practice-based learning and improvement (OR, 2.7; 95% CI, 1.7-4.4), interpersonal and communication skills (OR, 1.9; 95% CI, 1.2-3.0), and professionalism (OR, 2.5; 95% CI, 1.5-4.0).
CONCLUSION: Residency program directors' reactions to ACGME duty hour recommendations demonstrate a marked degree of concern about educating a competent generation of future physicians in the face of increasing duty hour standards and regulation.
The reactions of residency program directors to the ACGME duty hour recommendations demonstrate a marked degree of concern about educating a competent generation of future physicians in the face of increasing duty hour standards and regulation.
doi:10.4065/mcp.2010.0635
PMCID: PMC3046937  PMID: 21307391
18.  Factors Influencing Cancer Risk Perception in High Risk Populations: A Systematic Review 
Background
Patients at higher than average risk of heritable cancer may process risk information differently than the general population. However, little is known about clinical, demographic, or psychosocial predictors that may impact risk perception in these groups. The objective of this study was to characterize factors associated with perceived risk of developing cancer in groups at high risk for cancer based on genetics or family history.
Methods
We searched Ovid MEDLINE, Ovid Embase, Ovid PsycInfo, and Scopus from inception through April 2009 for English-language, original investigations in humans using core concepts of "risk" and "cancer." We abstracted key information and then further restricted articles dealing with perceived risk of developing cancer due to inherited risk.
Results
Of 1028 titles identified, 53 articles met our criteria. Most (92%) used an observational design and focused on women (70%) with a family history of or contemplating genetic testing for breast cancer. Of the 53 studies, 36 focused on patients who had not had genetic testing for cancer risk, 17 included studies of patients who had undergone genetic testing for cancer risk. Family history of cancer, previous prophylactic tests and treatments, and younger age were associated with cancer risk perception. In addition, beliefs about the preventability and severity of cancer, personality factors such as "monitoring" personality, the ability to process numerical information, as well as distress/worry also were associated with cancer risk perception. Few studies addressed non-breast cancer or risk perception in specific demographic groups (e.g. elderly or minority groups) and few employed theory-driven analytic strategies to decipher interrelationships of factors.
Conclusions
Several factors influence cancer risk perception in patients at elevated risk for cancer. The science of characterizing and improving risk perception in cancer for high risk groups, although evolving, is still relatively undeveloped in several key topic areas including cancers other than breast and in specific populations. Future rigorous risk perception research using experimental designs and focused on cancers other than breast would advance the field.
doi:10.1186/1897-4287-9-2
PMCID: PMC3118965  PMID: 21595959
19.  Dietary Modulation of Drosophila Sleep-Wake Behaviour 
PLoS ONE  2010;5(8):e12062.
Background
A complex relationship exists between diet and sleep but despite its impact on human health, this relationship remains uncharacterized and poorly understood. Drosophila melanogaster is an important model for the study of metabolism and behaviour, however the effect of diet upon Drosophila sleep remains largely unaddressed.
Methodology/Principal Findings
Using automated behavioural monitoring, a capillary feeding assay and pharmacological treatments, we examined the effect of dietary yeast and sucrose upon Drosophila sleep-wake behaviour for three consecutive days. We found that dietary yeast deconsolidated the sleep-wake behaviour of flies by promoting arousal from sleep in males and shortening periods of locomotor activity in females. We also demonstrate that arousal from nocturnal sleep exhibits a significant ultradian rhythmicity with a periodicity of 85 minutes. Increasing the dietary sucrose concentration from 5% to 35% had no effect on total sucrose ingestion per day nor any affect on arousal, however it did lengthen the time that males and females remained active. Higher dietary sucrose led to reduced total sleep by male but not female flies. Locomotor activity was reduced by feeding flies Metformin, a drug that inhibits oxidative phosphorylation, however Metformin did not affect any aspects of sleep.
Conclusions
We conclude that arousal from sleep is under ultradian control and regulated in a sex-dependent manner by dietary yeast and that dietary sucrose regulates the length of time that flies sustain periods of wakefulness. These findings highlight Drosophila as an important model with which to understand how diet impacts upon sleep and wakefulness in mammals and humans.
doi:10.1371/journal.pone.0012062
PMCID: PMC2919389  PMID: 20706579
20.  Interfacing systems biology and synthetic biology 
Genome Biology  2009;10(6):309.
A report of BioSysBio 2009, the IET conference on Synthetic Biology, Systems Biology and Bioinformatics, Cambridge, UK, 23-25 March 2009.
A report of BioSysBio 2009, the IET conference on Synthetic Biology, Systems Biology and Bioinformatics, Cambridge, UK, 23-25 March 2009.
doi:10.1186/gb-2009-10-6-309
PMCID: PMC2718492  PMID: 19591648
22.  Evaluation of Clustering and Genotype Distribution for Replication in Genome Wide Association Studies: The Age-Related Eye Disease Study 
PLoS ONE  2008;3(11):e3813.
Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations with low p-values, but few are replicated in subsequent studies. We sought to determine if characteristics of the genomic loci associated with a trait could be used to identify initial associations with a higher chance of replication in a second cohort. Data from the age-related eye disease study (AREDS) of 100,000 SNPs on 395 subjects with and 198 without age-related macular degeneration (AMD) were employed. Loci highly associated with AMD were characterized based on the distribution of genotypes, level of significance, and clustering of adjacent SNPs also associated with AMD suggesting linkage disequilibrium or multiple effects. Forty nine loci were highly associated with AMD, including 3 loci (CFH, C2/BF, LOC387715/HTRA1) already known to contain important genetic risks for AMD. One additional locus (C3) reported during the course of this study was identified and replicated in an additional study group. Tag-SNPs and haplotypes for each locus were evaluated for association with AMD in additional cohorts to account for population differences between discovery and replication subjects, but no additional clearly significant associations were identified. Relying on a significant genotype tests using a log-additive model would have excluded 57% of the non-replicated and none of the replicated loci, while use of other SNP features and clustering might have missed true associations.
doi:10.1371/journal.pone.0003813
PMCID: PMC2583911  PMID: 19043567
23.  A genome wide analysis of the response to uncapped telomeres in budding yeast reveals a novel role for the NAD+ biosynthetic gene BNA2 in chromosome end protection 
Genome Biology  2008;9(10):R146.
NAD+ metabolism may be linked to telomere end protection in yeast.
Background
Telomeres prevent the ends of eukaryotic chromosomes from being recognized as damaged DNA and protect against cancer and ageing. When telomere structure is perturbed, a co-ordinated series of events promote arrest of the cell cycle so that cells carrying damaged telomeres do not divide. In order to better understand the eukaryotic response to telomere damage, budding yeast strains harboring a temperature sensitive allele of an essential telomere capping gene (cdc13-1) were subjected to a transcriptomic study.
Results
The genome-wide response to uncapped telomeres in yeast cdc13-1 strains, which have telomere capping defects at temperatures above approximately 27°C, was determined. Telomere uncapping in cdc13-1 strains is associated with the differential expression of over 600 transcripts. Transcripts affecting responses to DNA damage and diverse environmental stresses were statistically over-represented. BNA2, required for the biosynthesis of NAD+, is highly and significantly up-regulated upon telomere uncapping in cdc13-1 strains. We find that deletion of BNA2 and NPT1, which is also involved in NAD+ synthesis, suppresses the temperature sensitivity of cdc13-1 strains, indicating that NAD+ metabolism may be linked to telomere end protection.
Conclusions
Our data support the hypothesis that the response to telomere uncapping is related to, but distinct from, the response to non-telomeric double-strand breaks. The induction of environmental stress responses may be a conserved feature of the eukaryotic response to telomere damage. BNA2, which is involved in NAD+ synthesis, plays previously unidentified roles in the cellular response to telomere uncapping.
doi:10.1186/gb-2008-9-10-r146
PMCID: PMC2760873  PMID: 18828915
24.  Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study 
BMC Genetics  2003;4(Suppl 1):S83.
The relationship between elevated blood pressure and cardiovascular and cerebrovascular disease risk is well accepted. Both systolic and diastolic hypertension are associated with this risk increase, but systolic blood pressure appears to be a more important determinant of cardiovascular risk than diastolic blood pressure. Subjects for this study are derived from the Framingham Heart Study data set. Each subject had five records of clinical data of which systolic blood pressure, age, height, gender, weight, and hypertension treatment were selected to characterize the phenotype in this analysis.
We modeled systolic blood pressure as a function of age using a mixed modeling methodology that enabled us to characterize the phenotype for each individual as the individual's deviation from the population average rate of change in systolic blood pressure for each year of age while controlling for gender, body mass index, and hypertension treatment. Significant (p = 0.00002) evidence for linkage was found between this normalized phenotype and a region on chromosome 1. Similar linkage results were obtained when we estimated the phenotype while excluding values obtained during hypertension treatment. The use of linear mixed models to define phenotypes is a methodology that allows for the adjustment of the main factor by covariates. Future work should be done in the area of combining this phenotype estimation directly with the linkage analysis so that the error in estimating the phenotype can be properly incorporated into the genetic analysis, which, at present, assumes that the phenotype is measured (or estimated) without error.
doi:10.1186/1471-2156-4-S1-S83
PMCID: PMC1866523  PMID: 14975151
25.  Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons 
Nature Communications  2014;5:4760.
Alternative splicing—the production of multiple messenger RNA isoforms from a single gene—is regulated in part by RNA binding proteins. While the RBPs transformer2 alpha (Tra2α) and Tra2β have both been implicated in the regulation of alternative splicing, their relative contributions to this process are not well understood. Here we find simultaneous—but not individual—depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α–Tra2β control. Target exons are enriched in genes associated with chromosome biology including CHEK1, which encodes a key DNA damage response protein. Dual Tra2 protein depletion reduces expression of full-length CHK1 protein, results in the accumulation of the DNA damage marker γH2AX and decreased cell viability. We conclude Tra2 proteins jointly control constitutive and alternative splicing patterns via paralog compensation to control pathways essential to the maintenance of cell viability.
RNA binding proteins are key regulators of alternative splicing. Here, Best et al. show that the human Tra2α and Tra2ß RNA binding proteins jointly contribute to the control of constitutive and alternative splicing events to regulate essential biological processes including the response to DNA damage.
doi:10.1038/ncomms5760
PMCID: PMC4175592  PMID: 25208576

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