Lisa Martin | University of Cincinnati College of Medicine (original) (raw)

Papers by Lisa Martin

Frontiers in Public Health

Background: Biobanks can accelerate research by providing researchers with samples and data. Howe... more Background: Biobanks can accelerate research by providing researchers with samples and data. However, hospital-based recruitment as a source for controls may create bias as who comes to the hospital may be different from the broader population.Methods: In an effort to broadly improve the quality of research studies and reduce costs and challenges associated with recruitment and sample collection, a group of diverse researchers at Cincinnati Children's Hospital Medical Center led an institution-supported initiative to create a population representative pediatric “Greater Cincinnati Childhood Cohort (GCC).” Participants completed a detailed survey, underwent a brief physician-led physical exam, and provided blood, urine, and hair samples. DNA underwent high-throughput genotyping.Results: In total, 1,020 children ages 3–18 years living in the 7 county Greater Cincinnati Metropolitan region were recruited. Racial composition of the cohort was 84% non-Hispanic white, 15% non-Hispanic...

Hypertension (Dallas, Tex. : 1979), 2018

Ambulatory blood pressure (BP) monitoring provides a more precise measure of BP status than clini... more Ambulatory blood pressure (BP) monitoring provides a more precise measure of BP status than clinic BP and is currently recommended in the evaluation of high BP in children and adolescents. However, ambulatory BP monitoring may not always be available. Our aim was to determine the clinic BP percentile most likely to predict ambulatory hypertension. We evaluated clinic and ambulatory BP in 247 adolescents (median age, 15.7 years; 63% white; 54% male). Clinic BP percentile (based on the fourth report and the 2017 American Academy of Pediatrics clinical practice guidelines) and ambulatory BP status (normal versus hypertension) were determined by age-, sex-, and height-specific cut points. Sensitivity and specificity of different clinic BP percentiles and cutoffs to predict ambulatory hypertension were calculated. Forty (16%) and 67 (27%) patients had systolic hypertension based on the fourth report and the 2017 guidelines, respectively, whereas 38 (15%) had wake ambulatory systolic hype...

Blood Pressure Monitoring

Ambulatory blood pressure monitoring (ABPM) provides a more precise assessment of blood pressure ... more Ambulatory blood pressure monitoring (ABPM) provides a more precise assessment of blood pressure (BP) status than clinic BP and is currently recommended in the evaluation of elevated BP in children and adolescents. Yet, ABPM can be uncomfortable for patients and cumbersome to perform. Evaluation of the tolerability to ABPM in 232 adolescent participants (median age: 15.7 years, 64% white, 16% Hispanic, 53% male) in the Study of Hypertension In Pediatrics Adult Hypertension Onset in Youth and its potential effects on ABPM results. Ambulatory BP status (normal vs. hypertension) was determined by sex and height-specific pediatric cut-points. Participants were asked to rank their wake and sleep tolerability to ABPM from 1 (most tolerant) to 10 (least tolerant); those with tolerability score of at least 8 were considered ABPM intolerant. Forty-three (19%) participants had wake ambulatory hypertension (HTN), 42 (18%) had sleep ambulatory HTN, and 64 (28%) had overall (wake and/or sleep) ambulatory HTN. Forty (17%) participants were intolerant to ABPM during wake hours and 58 (25%) were intolerant during sleep. ABPM intolerance during wake (but not sleep) hours was independently associated with wake (odds ratio: 2.34, 95% confidence interval: 1.01-5.39) and overall (odds ratio: 2.94, 95% confidence interval: 1.21-7.18) ambulatory HTN. Poor tolerability to ABPM is associated with a higher prevalence of ambulatory HTN in adolescents, and should be taken into consideration at time of ABPM interpretation.

Journal of Child and Adolescent Psychopharmacology

Hypertension (Dallas, Tex. : 1979), Jan 9, 2018

Although hypertension is identifiable in children and adolescents, there are many knowledge gaps ... more Although hypertension is identifiable in children and adolescents, there are many knowledge gaps on how to best define and manage high blood pressure in the young. SHIP-AHOY (Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth) is being conducted to address these knowledge gaps. Five hundred adolescents will be recruited and will undergo ambulatory blood pressure monitoring, echocardiographic, vascular, and cognitive assessments, as well as epigenetic studies to identify mechanisms that underlie the development of hypertensive target organ damage. Details of the design and methods that will be utilized in SHIP-AHOY are presented here, as well as baseline characteristics of the first 264 study participants. The primary aim of the study is to develop a risk-based definition of hypertension in the young that will result in better understanding of the transition from blood pressure in youth to adult cardiovascular disease.

Genes and immunity, Jan 8, 2018

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by im... more Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1214 subjects with EoE of European ancestry and 3734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS. We found lack of association of EoE with the genetic variants in the major histocompatibility complex (MHC) class I, II, and III genes and nearly all other loci using a highly powered study design with dense genotyping throughout the locus. Importantly, we identified an EoE risk locus at 16p13 with genome-wide significance (P=2.05 × 10, odds ratio = 0.76-0.81). This region is known to encode ...

Pediatric cardiology, Jan 22, 2018

Hypoplastic left heart syndrome (HLHS) is one of the most lethal congenital heart defects, and re... more Hypoplastic left heart syndrome (HLHS) is one of the most lethal congenital heart defects, and remains clinically challenging. While surgical palliation allows most HLHS patients to survive their critical heart disease with a single-ventricle physiology, many will suffer heart failure, requiring heart transplantation as the only therapeutic course. Current paradigm suggests HLHS is largely of hemodynamic origin, but recent findings from analysis of the first mouse model of HLHS showed intrinsic cardiomyocyte proliferation and differentiation defects underlying the left ventricular (LV) hypoplasia. The findings of similar defects of lesser severity in the right ventricle suggest this could contribute to the heart failure risks in surgically palliated HLHS patients. Analysis of 8 independent HLHS mouse lines showed HLHS is genetically heterogeneous and multigenic in etiology. Detailed analysis of the Ohia mouse line accompanied by validation studies in CRISPR gene-targeted mice reveal...

Journal of neurotrauma, Jan 2, 2018

This study examined whether the ankyrin repeat and kinase domain containing 1 gene (ANKK1) C/T si... more This study examined whether the ankyrin repeat and kinase domain containing 1 gene (ANKK1) C/T single-nucleotide polymorphism (SNP) rs1800497 moderated the association of family environment with long-term executive function (EF) following traumatic injury in early childhood. Caregivers of children with traumatic brain injury (TBI) and children with orthopedic injury (OI) completed the Behavior Rating Inventory of Executive Function (BRIEF) at post injury visits. DNA was collected to identify the rs1800497 genotype in the ANKK1 gene. General linear models examined gene-environment interactions as moderators of the effects of TBI on EF at two times post injury (12 months and 7 years). At 12 months post injury, analyses revealed a significant 3-way interaction of genotype with level of permissive parenting and injury type. Post-hoc analyses showed genetic effects were more pronounced for children with TBI from more positive family environments, such that children with TBI who were carr...

Hospital pediatrics, Jan 15, 2018

Large-scale, multisite studies in which researchers evaluate patient- and systems-level factors a... more Large-scale, multisite studies in which researchers evaluate patient- and systems-level factors associated with pediatric asthma exacerbation outcomes are lacking. We sought to investigate patient-level risks and system-level practices related to physiologic readiness for discharge (PRD) in the prospective Ohio Pediatric Asthma Repository. Participants were children ages 2 to 17 years admitted to an Ohio Pediatric Asthma Repository hospital for asthma exacerbation. Demographics, disease characteristics, and individual hospital practices were collected. The primary outcome was PRD timing (hours from admission or emergency department [ED] presentation until the first 4-hour albuterol spacing). Data for 1005 participants were available (865 ED presentations). Several nonstandard care practices were associated with time to PRD ( < .001). Continuous pulse oximetry was associated with increased time to PRD ( = .004). ED dexamethasone administration was associated with decreased time to...

The Journal of allergy and clinical immunology, Jan 26, 2018

The Journal of allergy and clinical immunology, Jan 12, 2017

Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly inc... more Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly increasing incidence of EoE suggests that environmental factors contribute to disease development. We tested for gene-environment interaction between EoE-predisposing polymorphisms (within TSLP, LOC283710/KLF13, CAPN14, CCL26, and TGFB) and implicated early-life factors (antibiotic use in infancy, cesarean delivery, breast-feeding, neonatal intensive care unit [NICU] admission, and absence of pets in the home). We conducted a case-control study using hospital-based cases (n = 127) and control subjects representative of the hospital catchment area (n = 121). We computed case-only interaction tests and in secondary analyses evaluated the combined and independent effects of genotype and environmental factors on the risk of EoE. Case-only analyses identified interactions between rs6736278 (CAPN14) and breast-feeding (P = .02) and rs17815905 (LOC283710/KLF13) and NICU admission (P = .02) but not...

Pulmonary circulation

Pulmonary arterial hypertension (PAH) is characterized by obstruction of pre-capillary pulmonary ... more Pulmonary arterial hypertension (PAH) is characterized by obstruction of pre-capillary pulmonary arteries, which leads to sustained elevation of pulmonary arterial pressure. Identifying those at risk through early interventions, such as genetic testing, may mitigate disease course. Current practice guidelines recommend genetic counseling and offering genetic testing to individuals with heritable PAH, idiopathic PAH, and their family members. However, it is unclear if PAH specialists follow these recommendations. Thus, our research objective was to determine PAH specialists' knowledge, utilization, and perceptions about genetic counseling and genetic testing. A survey was designed and distributed to PAH specialists who primarily work in the USA to assess their knowledge, practices, and attitudes about the genetics of PAH. Participants' responses were analyzed using parametric and non-parametric statistics and groups were compared using the Wilcoxon rank sum test. PAH speciali...

The Journal of allergy and clinical immunology, Jan 7, 2017

Multiple lines of evidence point to the potential importance of early-life environmental factors ... more Multiple lines of evidence point to the potential importance of early-life environmental factors in the rapid increase in the incidence of eosinophilic esophagitis (EoE), but potential exposures have not been extensively studied. We sought to assess the association between prenatal, intrapartum, and postnatal factors and the development of pediatric EoE using a case-control study. Patients with EoE were recruited from an existing registry at Cincinnati Children's Hospital Medical Center (CCHMC). Population-based community control subjects were identified from a separate CCHMC registry. Mothers of study subjects were contacted and completed a Web-based questionnaire. Crude and adjusted models were used to estimate associations. Mothers of 127 cases and 121 control subjects were included. We observed a positive association between several early-life factors and EoE, including prenatal (maternal fever: adjusted odds ratio [aOR], 3.18; 95% CI, 1.27-7.98; preterm labor: aOR, 2.18; 95...

Journal of neurotrauma, Jan 3, 2017

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. I... more Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. It is linked with a number of medical, neurological, cognitive, and behavioral sequelae. The influence of genetic factors on the biology and related recovery after TBI is poorly understood. Studies that seek to elucidate the impact of genetic influences on neurorecovery after TBI will lead to better individualization of prognosis and inform development of novel treatments, which are considerably lacking. Current genetic studies related to TBI have focused on specific candidate genes. The objectives of this study were to use a system biology-based approach to identify biologic processes over-represented with genetic variants previously implicated in clinical outcomes after TBI and identify unique genes potentially related to recovery after TBI. After performing a systematic review to identify genes in the literature associated with clinical outcomes, we used the genes identified to perform...

Journal of neurotrauma, 2017

The present study examined the association of dopamine-related genes with short- and long-term ne... more The present study examined the association of dopamine-related genes with short- and long-term neurobehavioral recovery, as well as neurobehavioral recovery trajectories over time, in children who had sustained early childhood traumatic brain injuries (TBI) relative to children who had sustained orthopedic injuries (OI). Participants were recruited from a prospective, longitudinal study evaluating outcomes of children who sustained a TBI (n = 68) or OI (n = 72) between the ages of 3 and 7 years. Parents completed ratings of child executive function and behavior at the immediate post-acute period (0-3 months after injury); 6, 12, and 18 months after injury; and an average of 3.5 and 7 years after injury. Thirty-two single nucleotide polymorphisms (SNPs) in dopamine-related genes (dopamine receptor D2 [DRD2], solute carrier family 6 member 3 [SLC6A3], solute carrier family 18 member A2 [SLC18A2], catechol-o-methyltransferase [COMT], and ankyrin repeat and kinase domain containing 1 [A...

Circulation. Cardiovascular genetics, 2017

Although dichotomous criteria for the metabolic syndrome (MetS) appear heritable, it is not known... more Although dichotomous criteria for the metabolic syndrome (MetS) appear heritable, it is not known whether MetS severity as assessed by a continuous MetS score is heritable and whether this varies by race. We used SOLAR (Sequential Oligogenic Linkage Analysis Routines) to evaluate heritability of Adult Treatment Panel-III MetS and a sex- and race-specific MetS severity Z score among 3 large familial cohorts: the JHS (Jackson Heart Study, 1404 black participants), TOPS (Take Off Pounds Sensibly, 1947 white participants), and PLRS (Princeton Lipid Research Study, 229 black and 527 white participants). Heritability estimates were larger for Adult Treatment Panel-III MetS among black compared with white cohort members (JHS 0.48; 95% confidence interval [CI], 0.28-0.68 and PLRS blacks 0.93 [95% CI, 0.73-1.13] versus TOPS 0.21 [95% CI, -0.18 to 0.60] and PLRS whites 0.27 [95% CI, -0.04 to 0.58]). The difference by race narrowed when assessing heritability of the MetS severity score (JHS 0....

Pharmacogenomics and personalized medicine, 2017

The perioperative pain experience shows great interindividual variability and is difficult to pre... more The perioperative pain experience shows great interindividual variability and is difficult to predict. The mu-1 opioid receptor gene (OPRM1) is known to play an important role in opioid-pain pathways. Since deoxyribonucleic acid (DNA) methylation is a potent repressor of gene expression, DNA methylation was evaluated at the OPRM1 promoter, as a predictor of preoperative, acute, and chronic postsurgical pain (CPSP). A prospective observational cohort study was conducted in 133 adolescents with idiopathic scoliosis undergoing spine fusion under standard protocols. Data regarding pain, opioid consumption, anxiety, and catastrophizing (using validated questionnaires) were collected before and 2-3 months postsurgery. Outcomes evaluated were preoperative pain, acute postoperative pain (area under curve [AUC] for pain scores over 48 hours), and CPSP (numerical rating scale >3/10 at 2-3 months postsurgery). Blood samples collected preoperatively were analyzed for DNA methylation by pyros...

Pharmacogenomics, Jan 4, 2017

Large interindividual variability in morphine pharmacokinetics (PK) could contribute to variabili... more Large interindividual variability in morphine pharmacokinetics (PK) could contribute to variability in morphine analgesia and adverse events. Respiratory depression (RD) and postoperative nausea and vomiting (PONV) are significant adverse drug response of intravenous morphine in the perioperative setting limiting its efficacy in achieving adequate surgical pain relief. OCT1 is a transporter in the liver that transports morphine from the bloodstream into hepatocytes. Earlier we reported association of genetic polymorphisms in OCT1 with morphine PK, and lower morphine clearance in Caucasian children as compared with African-American (AA) children. The aim of this study is to identify the association between common OCT1 genotypes affecting morphine's PK and clinically important postoperative morphine-related adverse outcomes. After obtaining institutional review board (IRB) approval and informed consents, 311 children ages 6-15 years, American Society of Anesthesiologists' phys...

The Journal of allergy and clinical immunology, Jan 24, 2017

RATIONALE: Complement, coagulation and remodelling pathways have been implicated in the pathogene... more RATIONALE: Complement, coagulation and remodelling pathways have been implicated in the pathogenesis of allergic rhinitis. We sought to further characterise these responses through analysis of mucosal mediators in the nasal allergen challenge (NAC) model. METHODS: Sixteen volunteers allergic to Timothy grass pollen, as determined by skin prick testing, had NAC performed outside the allergy season. Nasal mucosal lining fluid (MLF) was sampled by nasosorption at baseline, repeatedly in the first hour, and then up to 8 hours post-NAC. Mediators of the complement, coagulation and fibrinolysis pathways were analysed by immunoassay. RESULTS: Levels of anaphylatoxins, such as C5a, increased from a baseline median of 45.2pg/ml, peaked at 1175pg/ml at 30 minutes post-NAC (P<0.0001), and remained elevated in the late phase. Activation of coagulation and fibrinolysis was also evident, where levels of the fibrin degradation product D-dimer were rapidly elevated, up to 85 fold above baseline by 45 minutes (P50.0002). Interestingly, a second peak of D-dimer levels was observed at 8 hours (P50.0002), coinciding with elevated urokinase levels. This biphasic profile was similarly observed in mediators associated with fibrosis, including adiponectin and surfactant protein-D. CONCLUSIONS: We demonstrate that complement and fibrinolysis are elements of the nasal allergic response to grass allergen, occurring in parallel with the well documented activation of mast cells and type-II inflammation. These cascades are intrinsically associated with acute inflammatory responses, and it will be of interest to assess the role of these mediators in relation to a range of respiratory diseases.

Nature, Mar 22, 2017

Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosi... more Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects...