Browsing by Author "Kollins, Scott H"
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Item Open Access Cannabinoid exposure and altered DNA methylation in rat and human sperm.(Epigenetics, 2018-01) Murphy, Susan K; Itchon-Ramos, Nilda; Visco, Zachary; Huang, Zhiqing; Grenier, Carole; Schrott, Rose; Acharya, Kelly; Boudreau, Marie-Helene; Price, Thomas M; Raburn, Douglas J; Corcoran, David L; Lucas, Joseph E; Mitchell, John T; McClernon, F Joseph; Cauley, Marty; Hall, Brandon J; Levin, Edward D; Kollins, Scott HLittle is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.Item Open Access Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm.(Epigenetics, 2020-01) Schrott, Rose; Acharya, Kelly; Itchon-Ramos, Nilda; Hawkey, Andrew B; Pippen, Erica; Mitchell, John T; Kollins, Scott H; Levin, Edward D; Murphy, Susan KParental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.Item Open Access Correction to: The role of machine learning in clinical research: transforming the future of evidence generation.(Trials, 2021-09) Weissler, E Hope; Naumann, Tristan; Andersson, Tomas; Ranganath, Rajesh; Elemento, Olivier; Luo, Yuan; Freitag, Daniel F; Benoit, James; Hughes, Michael C; Khan, Faisal; Slater, Paul; Shameer, Khader; Roe, Matthew; Hutchison, Emmette; Kollins, Scott H; Broedl, Uli; Meng, Zhaoling; Wong, Jennifer L; Curtis, Lesley; Huang, Erich; Ghassemi, MarzyehFollowing the publication of the original article [1], we were notified that current affiliations 17, 18 and 19 were erroneously added to the first author rather than the senior author (Marzyeh Ghassemi). The original article has now been corrected.Item Open Access DNA Methylation in Babies Born to Nonsmoking Mothers Exposed to Secondhand Smoke during Pregnancy: An Epigenome-Wide Association Study.(Environmental health perspectives, 2021-05-19) Fuemmeler, Bernard F; Dozmorov, Mikhail G; Do, Elizabeth K; Zhang, Junfeng Jim; Grenier, Carole; Huang, Zhiqing; Maguire, Rachel L; Kollins, Scott H; Hoyo, Cathrine; Murphy, Susan KBackground
Maternal smoking during pregnancy is related to altered DNA methylation in infant umbilical cord blood. The extent to which low levels of smoke exposure among nonsmoking pregnant women relates to offspring DNA methylation is unknown.Objective
This study sought to evaluate relationships between maternal prenatal plasma cotinine levels and DNA methylation in umbilical cord blood in newborns using the Infinium HumanMethylation 450K BeadChip.Methods
Participants from the Newborn Epigenetics Study cohort who reported not smoking during pregnancy had verified low levels of cotinine from maternal prenatal plasma (0 ng/mL to <4 ng/mL), and offspring epigenetic data from umbilical cord blood were included in this study (n=79). Multivariable linear regression models were fit to the data, controlling for cell proportions, age, race, education, and parity. Estimates represent changes in response to any 1-ng/mL unit increase in exposure.Results
Multivariable linear regression models yielded 29,049 CpGs that were differentially methylated in relation to increases in cotinine at a 5% false discovery rate. Top CpGs were within or near genes involved in neuronal functioning (PRKG1, DLGAP2, BSG), carcinogenesis (FHIT, HSPC157) and inflammation (AGER). Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggest cotinine was related to methylation of gene pathways controlling neuronal signaling, metabolic regulation, cell signaling and regulation, and cancer. Further, enhancers associated with transcription start sites were enriched in altered CpGs. Using an independent sample from the same study population (n=115), bisulfite pyrosequencing was performed with infant cord blood DNA for two genes within our top 20 hits (AGER and PRKG1). Results from pyrosequencing replicated epigenome results for PRKG1 (cg17079497, estimate=-1.09, standard error (SE)=0.45, p=0.018) but not for AGER (cg09199225; estimate=-0.16, SE=0.21, p=0.44).Discussion
Secondhand smoke exposure among nonsmoking women may alter DNA methylation in regions involved in development, carcinogenesis, and neuronal functioning. These novel findings suggest that even low levels of smoke exposure during pregnancy may be sufficient to alter DNA methylation in distinct sites of mixed umbilical cord blood leukocytes in pathways that are known to be altered in cord blood from pregnant active smokers. https://doi.org/10.1289/EHP8099.Item Open Access Effect of Prenatal Smoke Exposure on Birth Weight: The Moderating Role of Maternal Depressive Symptoms.(Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2018-12-24) Schechter, Julia; Do, Elizabeth K; Zhang, Junfeng Jim; Hoyo, Cathrine; Murphy, Susan K; Kollins, Scott H; Fuemmeler, BernardIntroduction:Both prenatal smoke exposure and depression have been linked to lower birth weight, a risk factor for morbidity and mortality. Few studies have looked at the interaction between these risk factors and none have used a biomarker to objectively measure prenatal smoke exposure. The current study sought to examine independent and interactive effects of cotinine and depression on birth weight. The effect of race was also explored. Method:Data were drawn from a prospective study of pregnant women (N=568) in the southeastern U.S. Maternal demographic, health information, depressive symptoms, and birth data were collected via self-report and medical record abstraction. Prenatal blood samples were assayed for cotinine. Results:Controlling for covariates, multiple regression analyses indicated that both cotinine and depressive symptoms independently predicted lower birth weight and a significant interaction was also observed. Upon probing the interaction, a negative association between cotinine levels and birth weight was found in the context of higher depression but not lower depression scores. Similarly, logistic regression analyses revealed a significant interaction between cotinine and depression, such that cotinine predicted having a baby < 2500 g among women who fell above the indicated cut-off score. African American women had the highest levels of cotinine and lowest weight babies; however, race was not a significant moderator. Conclusions:Results suggest prenatal smoke exposure has a greater negative effect on birth weight for women endorsing co-occurring depressive symptoms. Findings can inform targeted interventions and assist medical providers with identifying women at increased risk for poor perinatal outcomes. Implications:Despite the common occurrence of smoking during pregnancy and prenatal depression, the interaction between these risk factors on birth weight has rarely been examined. Further, the extant results have been mixed, likely due in part to difficulties in measurement. The current study was the first to use prenatal cotinine to assess bias-free, continuous levels of prenatal smoke exposure. Results indicate that prenatal cotinine was a significant predictor of birth weight only in the context of maternal depressive symptoms. These findings have important implications for mitigating negative perinatal outcomes for pregnant women and their children.Item Open Access "I Use Weed for My ADHD": A Qualitative Analysis of Online Forum Discussions on Cannabis Use and ADHD.(PLoS One, 2016) Mitchell, John T; Sweitzer, Maggie M; Tunno, Angela M; Kollins, Scott H; McClernon, F JosephBACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for problematic cannabis use. However, clinical and anecdotal evidence suggest an increasingly popular perception that cannabis is therapeutic for ADHD, including via online resources. Given that the Internet is increasingly utilized as a source of healthcare information and may influence perceptions, we conducted a qualitative analysis of online forum discussions, also referred to as threads, on the effects of cannabis on ADHD to systematically characterize the content patients and caregivers may encounter about ADHD and cannabis. METHODS: A total of 268 separate forum threads were identified. Twenty percent (20%) were randomly selected, which yielded 55 separate forum threads (mean number of individual posts per forum thread = 17.53) scored by three raters (Cohen's kappa = 0.74). A final sample of 401 posts in these forum threads received at least one endorsement on predetermined topics following qualitative coding procedures. RESULTS: Twenty-five (25%) percent of individual posts indicated that cannabis is therapeutic for ADHD, as opposed to 8% that it is harmful, 5% that it is both therapeutic and harmful, and 2% that it has no effect on ADHD. This pattern was generally consistent when the year of each post was considered. The greater endorsement of therapeutic versus harmful effects of cannabis did not generalize to mood, other (non-ADHD) psychiatric conditions, or overall domains of daily life. Additional themes emerged (e.g., cannabis being considered sanctioned by healthcare providers). CONCLUSIONS: Despite that there are no clinical recommendations or systematic research supporting the beneficial effects of cannabis use for ADHD, online discussions indicate that cannabis is considered therapeutic for ADHD-this is the first study to identify such a trend. This type of online information could shape ADHD patient and caregiver perceptions, and influence cannabis use and clinical care.Item Open Access Pre-Pregnancy Weight and Symptoms of Attention Deficit Hyperactivity Disorder and Executive Functioning Behaviors in Preschool Children.(International journal of environmental research and public health, 2019-02-25) Fuemmeler, Bernard F; Zucker, Nancy; Sheng, Yaou; Sanchez, Carmen E; Maguire, Rachel; Murphy, Susan K; Kollins, Scott H; Hoyo, CathrineThis study examines pre-pregnancy Body Mass Index (BMI) and gestational weight gain (GWG) in relation to early childhood Attention Deficit Hyperactivity Disorder (ADHD) symptoms and related executive self-regulation behaviors. The analyses sample (n = 331) included a subsample of participants from a birth cohort recruited from prenatal clinics and hospital facilities from April 2005 to June 2011 in Durham, North Carolina. Pre-pregnancy BMI was calculated from weight at the last menstrual period and height was extracted from medical records. Gestational weight gain was calculated from pre-pregnancy weight and weight measured at the time of delivery. ADHD symptoms and executive self-regulation behaviors were assessed by maternal report (mean age = 3 years). Multivariable regression methods with inverse probability weighting (IPW) were used to evaluate associations accounting for sample selection bias and confounding. Pre-pregnancy BMI at levels ≥35 was positively associated with higher ADHD symptoms and worse executive self-regulation behaviors (inhibitory control and attention). Compared to adequate GWG, less than adequate GWG was related to more ADHD hyperactive-impulsive symptoms, whereas greater than adequate GWG was related to more problematic behaviors related to working memory and planning. The findings support a link between maternal weight and child neurodevelopment. Continued research that help identify biological mechanisms are needed.Item Open Access Refraining from use diminishes cannabis-associated epigenetic changes in human sperm.(Environmental epigenetics, 2021-01) Schrott, Rose; Murphy, Susan K; Modliszewski, Jennifer L; King, Dillon E; Hill, Bendu; Itchon-Ramos, Nilda; Raburn, Douglas; Price, Thomas; Levin, Edward D; Vandrey, Ryan; Corcoran, David L; Kollins, Scott H; Mitchell, John TCannabis use alters sperm DNA methylation, but the potential reversibility of these changes is unknown. Semen samples from cannabis users and non-user controls were collected at baseline and again following a 77-day period of cannabis abstinence (one spermatogenic cycle). Users and controls did not significantly differ by demographics or semen analyses. Whole-genome bisulfite sequencing identified 163 CpG sites with significantly different DNA methylation in sperm between groups (P < 2.94 × 10-9). Genes associated with altered CpG sites were enriched with those involved in development, including cardiogenesis and neurodevelopment. Many of the differences in sperm DNA methylation between groups were diminished after cannabis abstinence. These results indicate that sustained cannabis abstinence significantly reduces the number of sperm showing cannabis-associated alterations at genes important for early development.Item Open Access The role of machine learning in clinical research: transforming the future of evidence generation.(Trials, 2021-08) Weissler, E Hope; Naumann, Tristan; Andersson, Tomas; Ranganath, Rajesh; Elemento, Olivier; Luo, Yuan; Freitag, Daniel F; Benoit, James; Hughes, Michael C; Khan, Faisal; Slater, Paul; Shameer, Khader; Roe, Matthew; Hutchison, Emmette; Kollins, Scott H; Broedl, Uli; Meng, Zhaoling; Wong, Jennifer L; Curtis, Lesley; Huang, Erich; Ghassemi, MarzyehBackground
Interest in the application of machine learning (ML) to the design, conduct, and analysis of clinical trials has grown, but the evidence base for such applications has not been surveyed. This manuscript reviews the proceedings of a multi-stakeholder conference to discuss the current and future state of ML for clinical research. Key areas of clinical trial methodology in which ML holds particular promise and priority areas for further investigation are presented alongside a narrative review of evidence supporting the use of ML across the clinical trial spectrum.Results
Conference attendees included stakeholders, such as biomedical and ML researchers, representatives from the US Food and Drug Administration (FDA), artificial intelligence technology and data analytics companies, non-profit organizations, patient advocacy groups, and pharmaceutical companies. ML contributions to clinical research were highlighted in the pre-trial phase, cohort selection and participant management, and data collection and analysis. A particular focus was paid to the operational and philosophical barriers to ML in clinical research. Peer-reviewed evidence was noted to be lacking in several areas.Conclusions
ML holds great promise for improving the efficiency and quality of clinical research, but substantial barriers remain, the surmounting of which will require addressing significant gaps in evidence.Item Open Access Validation of the Sleep Regularity Index in Older Adults and Associations with Cardiometabolic Risk.(Scientific reports, 2018-09-21) Lunsford-Avery, Jessica R; Engelhard, Matthew M; Navar, Ann Marie; Kollins, Scott HSleep disturbances, including insufficient sleep duration and circadian misalignment, confer risk for cardiometabolic disease. Less is known about the association between the regularity of sleep/wake schedules and cardiometabolic risk. This study evaluated the external validity of a new metric, the Sleep Regularity Index (SRI), among older adults (n = 1978; mean age 68.7 ± 9.2), as well as relationships between the SRI and cardiometabolic risk using data from the Multi-Ethnic Study of Atherosclerosis (MESA). Results indicated that sleep irregularity was associated with delayed sleep timing, increased daytime sleep and sleepiness, and reduced light exposure, but was independent of sleep duration. Greater sleep irregularity was also correlated with 10-year risk of cardiovascular disease and greater obesity, hypertension, fasting glucose, hemoglobin A1C, and diabetes status. Finally, greater sleep irregularity was associated with increased perceived stress and depression, psychiatric factors integrally tied to cardiometabolic disease. These results suggest that the SRI is a useful measure of sleep regularity in older adults. Additionally, sleep irregularity may represent a target for early identification and prevention of cardiometabolic disease. Future studies may clarify the causal direction of these effects, mechanisms underlying links between sleep irregularity and cardiometabolic risk, and the utility of sleep interventions in reducing cardiometabolic risk.