The Burden of Attention-Deficit/Hyperactivity Disorder in Adults: A Real-World Linked Data Study.

Objective: To assess the humanistic and economic burden of attention-deficit/hyperactivity disorder (ADHD) among adult patients treated with immediate-release (IR) only or extended-release (ER) only stimulants and those unmedicated versus treated with ER + IR stimulants.Methods: This study analyzed linked data from National Health and Wellness Survey and claims to assess the differences in patient characteristics and outcomes, including health-related quality of life (HRQoL), work productivity and activity impairment, and health care resource utilization (HRU) and associated costs by comparing ADHD patients treated with either IR or ER and those unmedicated for ADHD versus ER + IR.Results: The burden of ADHD was compared among adults on stimulant medications with different duration of effect (DoE) (ER + IR: n = 34, ER: n = 184, IR: n = 149) and the unmedicated group (n = 114). Bivariate analysis showed the IR (P = .047) and unmedicated groups (P = .01) had significantly lower Medical Outcomes Study 36-item Short Form physical component summary scores versus ER + IR. The unmedicated group had higher HRU and associated costs versus other groups. Multivariable analysis revealed that the unmedicated group had twice as many outpatient visits (P = .001) and higher total annual direct costs than those on ER + IR (risk ratio = 2.20, P = .016). Patients with mental health comorbidities had significantly poorer HRQoL mental component summary scores and higher activity impairment versus those without mental health comorbidities (P = .001 and P < .001, respectively).Conclusions: Patients with ADHD treated with longer DoE formulations had substantially better economic outcomes versus shorter DoE formulation or unmedicated groups, offering potential cost savings to the health care system and the patient. Furthermore, it is important to consider the effect of mental health comorbidities in the overall management of ADHD.

An Exploratory Analysis of Real-World End Points for Assessing Outcomes Among Immunotherapy-Treated Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSE: This pilot study examined the ability to operationalize the collection of real-world data to explore the potential use of real-world end points extracted from data from diverse health care data organizations and to assess how these relate to similar end points in clinical trials for immunotherapy-treated advanced non-small-cell lung cancer. PATIENTS AND METHODS: Researchers from six organizations followed a common protocol using data from administrative claims and electronic health records to assess real-world end points, including overall survival (rwOS), time to next treatment, time to treatment discontinuation (rwTTD), time to progression, and progression-free survival, among patients with advanced non-small-cell lung cancer treated with programmed death 1/programmed death-ligand 1 inhibitors in real-world settings. Data sets included from 269 to 6,924 patients who were treated between January 2011 and October 2017. Results from contributors were anonymized. RESULTS: Correlations between real-world intermediate end points (rwTTD and time to next treatment) and rwOS were moderate to high (range, 0.6 to 0.9). rwTTD was the most consistent end points as treatment detail was available in all data sets. rwOS at 1 year post-programmed death-ligand 1 initiation ranged from 40% to 57%. In addition, rwOS as assessed via electronic health records and claims data fell within the range of median OS values observed in relevant clinical trials. Data sources had been used extensively for research with ongoing data curation to assure accuracy and practical completeness before the initiation of this research. CONCLUSION: These findings demonstrate that real-world end points are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision making. Differences observed likely reflect true differences between real-world and protocol-driven practices.

A Patient-Reported Outcome Instrument to Assess Symptom Burden and Predict Survival in Patients with Advanced Cancer: Flipping the Paradigm to Improve Timing of Palliative and End-of-Life Discussions and Reduce Unwanted Health Care Costs.

BACKGROUND: Discussions regarding palliative care and end-of-life care issues are frequently delayed past the time of usefulness, resulting in unwanted medical care. We sought to develop a patient-reported outcome (PRO) instrument that allows patients to voice their symptom burdens and facilitate timing of discussions. SUBJECTS, MATERIALS, AND METHODS: A seven-item PRO instrument (Cota Patient Assessed Symptom Score-7 item [CPASS-7]) covering physical performance status, pain, burden, and depression was administered (September 2015 through October 2016) with correlation to overall survival, correcting for time to complete survey since diagnosis. RESULTS: A total of 1,191 patients completed CPASS-7 at a median of 560 days following the diagnosis of advanced cancer. Of these patients, 49% were concerned that they could not do the things they wanted; 35% reported decreased performance status. Financial toxicity was reported by 39% of patients, with family burdens noted in 25%. Although depression was reported by 15%, 43% reported lack of pleasure. Pain was reported by 33%. The median CPASS-7 total symptom burden score was 16 (possible 0-112). With a median follow-up of 15 months from initial survey, 46% had died. Patients with symptom burden scores <29 and ≥29 had a 6-month overall survival rate of 87% and 67%, respectively, and 12-month survival rates of 72% and 50%. A one-point score increase resulted in a 1.8% increase in expected hazard. CONCLUSION: Patients with advanced cancer with higher levels of symptom burden, as self-reported on the CPASS-7, had inferior survival. The PRO facilitates identification of patients appropriate for reassessment of treatment goals and potentially palliative and end-of-life care in response to symptom burden concerns. IMPLICATIONS FOR PRACTICE: A seven-item patient-reported outcome (PRO) instrument was administered to 1,191 patients with advanced cancers. Patients self-reporting higher levels of physical and psychological symptom burden had inferior overall survival rates. High individual item symptom PRO responses should serve as a useful trigger to initiate supportive interventions, but when scores indicate global problems, discussions regarding end-of-life care might be appropriate.

Genomic Profiling of Advanced Non-Small Cell Lung Cancer in Community Settings: Gaps and Opportunities.

BACKGROUND: National guidelines have advocated broad molecular profiling as a part of the standard diagnostic evaluation for advanced non-small cell lung cancer (NSCLC), with the goal of identifying driver mutations for which effective therapies or clinical trials are available. However, adherence to genomic testing guidelines could present challenges to community oncologists. PATIENTS AND METHODS: We performed a retrospective review of genomic testing patterns in patients with nonsquamous NSCLC treated by 89 oncologists at 15 sites throughout New Jersey and Maryland from January 2013 to December 2015. RESULTS: A total of 814 patients (89% with stage IV; 11% with stage IIIB) were identified in the COTA Inc database. Of the 814 patients, 479 (59%) met the guideline recommendations for EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) biomarker testing; 63 (8%) underwent comprehensive genomic profiling for all 4 major types of alterations (point mutations, indels, fusions, and copy number amplifications). Gender, age, race, site of care (referral vs. community center), and practice size did not influence comprehensive genomic profiling frequency. Active smokers and patients who died within 30 days were tested less frequently (P < .05). Among those not tested for EGFR and ALK, 52% received chemotherapy without documented reasons for no testing, 32% did not receive antineoplastic therapy, and 13% had insufficient tissue for genotyping. CONCLUSION: Genomic testing presents multiple logistical challenges for the community-based oncologist, including coordination of sample handling, long turnaround times, test reimbursement, access to targeted therapies, insufficient tissue, and patient harm from the repeat biopsies necessary if the tissue sample is insufficient. Opportunities exist for improvement in guideline adherence, possibly through new technologies such as "liquid biopsies," which obviates the need tissue biopsy samples in select settings.

Decline in serum hemoglobin in the 7 days after cardiac catheterization.

OBJECTIVES: Bleeding is an established complication following cardiac catheterization and lower preoperative hemoglobin concentration is a potentially modifiable risk factor for adverse outcomes after cardiac surgery. However, typical changes in serum hemoglobin concentration after cardiac catheterization are poorly defined. The authors sought to identify the pattern of change in serum hemoglobin concentration within 7 days after cardiovascular catheterization, factors associated with this change and any association with adverse outcomes. DESIGN: Retrospective observational study over a 1-year period. SETTING: U.S. academic medical institution. PARTICIPANTS: Participants were 284 adult patients with baseline hemoglobin concentration≥12 g/dL undergoing nonemergent cardiac surgery after cardiovascular catheterization via the femoral arterial route. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Lowest daily hemoglobin concentration was recorded where available for up to 7 days after catheterization and before surgery. Generalized estimating equations identified the pattern of change in serum hemoglobin while regression models identified factors associated with hemoglobin decline. Following cardiovascular catheterization average serum hemoglobin declined over time, reaching a nadir 1.4 g/dL (95% CI 1.0-1.8) below baseline 6 days after catheterization. A higher baseline hemoglobin concentration and lower body mass index were associated with greater maximal decline in hemoglobin concentration after catheterization. Acute preoperative hemoglobin decline was not associated with acute kidney injury (AKI) or a composite adverse outcome that may reflect organ ischemia. CONCLUSIONS: In a cohort of patients before cardiac surgery serum hemoglobin declines during the week after cardiac catheterization, with maximal average decline observed 5 to 7 days after catheterization.

Prenatal and postnatal bisphenol A exposure and asthma development among inner-city children.

BACKGROUND: Bisphenol A (BPA) is used widely to manufacture food container linings. Mouse models suggest exposure to BPA might increase allergic inflammation. OBJECTIVES: We hypothesized that BPA exposure, as assessed based on urinary BPA concentrations, would be associated with increased odds of wheeze and asthma and increased fraction of exhaled nitric oxide (Feno) values in children. METHODS: The Columbia Center for Children's Environmental Health recruited pregnant women for a prospective birth cohort study (n = 568). Mothers during the third trimester and children at ages 3, 5, and 7 years provided spot urine samples. Total urinary BPA concentrations were measured by using online solid-phase extraction, high-performance liquid chromatography, isotope-dilution tandem mass spectrometry. Wheeze in the last 12 months was measured by using questionnaires at ages 5, 6, and 7 years. Asthma was determined by a physician once between ages 5 and 12 years. Feno values were measured at ages 7 to 11 years. RESULTS: Prenatal urinary BPA concentrations were associated inversely with wheeze at age 5 years (odds ratio [OR], 0.7; 95% CI, 0.5-0.9; P = .02). Urinary BPA concentrations at age 3 years were associated positively with wheeze at ages 5 years (OR, 1.4; 95% CI, 1.1-1.8; P = .02) and 6 years (OR, 1.4; 95% CI, 1.0-1.9; P = .03). BPA concentrations at age 7 years were associated with wheeze at age 7 years (OR, 1.4; 95% CI, 1.0-1.9; P = .04) and Feno values (ß = 0.1; 95% CI, 0.02-0.2; P = .02). BPA concentrations at ages 3, 5, and 7 years were associated with asthma (OR, 1.5 [95% CI, 1.1-2.0], P = .005; OR, 1.4 [95% CI, 1.0-1.9], P = .03; and OR, 1.5 [95% CI, 1.0-2.1], P = .04, respectively). CONCLUSIONS: This is the first report of an association between postnatal urinary BPA concentrations and asthma in children.

Step detection in single-molecule real time trajectories embedded in correlated noise.

Single-molecule real time trajectories are embedded in high noise. To extract kinetic or dynamic information of the molecules from these trajectories often requires idealization of the data in steps and dwells. One major premise behind the existing single-molecule data analysis algorithms is the gaussian 'white' noise, which displays no correlation in time and whose amplitude is independent on data sampling frequency. This so-called 'white' noise is widely assumed but its validity has not been critically evaluated. We show that correlated noise exists in single-molecule real time trajectories collected from optical tweezers. The assumption of white noise during analysis of these data can lead to serious over- or underestimation of the number of steps depending on the algorithms employed. We present a statistical method that quantitatively evaluates the structure of the underlying noise, takes the noise structure into account, and identifies steps and dwells in a single-molecule trajectory. Unlike existing data analysis algorithms, this method uses Generalized Least Squares (GLS) to detect steps and dwells. Under the GLS framework, the optimal number of steps is chosen using model selection criteria such as Bayesian Information Criterion (BIC). Comparison with existing step detection algorithms showed that this GLS method can detect step locations with highest accuracy in the presence of correlated noise. Because this method is automated, and directly works with high bandwidth data without pre-filtering or assumption of gaussian noise, it may be broadly useful for analysis of single-molecule real time trajectories.

Reducing heavy drinking in HIV primary care: a randomized trial of brief intervention, with and without technological enhancement.

AIMS: In HIV-infected individuals, heavy drinking compromises survival. In HIV primary care, the efficacy of brief motivational interviewing (MI) to reduce drinking is unknown, alcohol-dependent patients may need greater intervention and resources are limited. Using interactive voice response (IVR) technology, HealthCall was designed to enhance MI via daily patient self-monitoring calls to an automated telephone system with personalized feedback. We tested the efficacy of MI-only and MI+HealthCall for drinking reduction among HIV primary care patients. DESIGN: Parallel random assignment to control (n = 88), MI-only (n = 82) or MI+HealthCall (n = 88). Counselors provided advice/education (control) or MI (MI-only or MI+HealthCall) at baseline. At 30 and 60 days (end-of-treatment), counselors briefly discussed drinking with patients, using HealthCall graphs with MI+HealthCall patients. SETTING: Large urban HIV primary care clinic. PARTICIPANTS: Patients consuming ≥4 drinks at least once in prior 30 days. MEASUREMENTS: Using time-line follow-back, primary outcome was number of drinks per drinking day, last 30 days. FINDINGS: End-of-treatment number of drinks per drinking day (NumDD) means were 4.75, 3.94 and 3.58 in control, MI-only and MI+HealthCall, respectively (overall model χ(2) , d.f. = 9.11,2, P = 0.01). For contrasts of NumDD, P = 0.01 for MI+HealthCall versus control; P = 0.07 for MI-only versus control; and P = 0.24 for MI+HealthCall versus MI-only. Secondary analysis indicated no intervention effects on NumDD among non-alcohol-dependent patients. However, for contrasts of NumDD among alcohol-dependent patients, P < 0.01 for MI+HealthCall versus control; P = 0.09 for MI-only versus control; and P = 0.03 for MI+HealthCall versus MI-only. By 12-month follow-up, although NumDD remained lower among alcohol-dependent patients in MI+HealthCall than others, effects were no longer significant. CONCLUSIONS: For alcohol-dependent HIV patients, enhancing MI with HealthCall may offer additional benefit, without extensive additional staff involvement.

Single-base pair unwinding and asynchronous RNA release by the hepatitis C virus NS3 helicase.

Nonhexameric helicases use adenosine triphosphate (ATP) to unzip base pairs in double-stranded nucleic acids (dsNAs). Studies have suggested that these helicases unzip dsNAs in single-base pair increments, consuming one ATP molecule per base pair, but direct evidence for this mechanism is lacking. We used optical tweezers to follow the unwinding of double-stranded RNA by the hepatitis C virus NS3 helicase. Single-base pair steps by NS3 were observed, along with nascent nucleotide release that was asynchronous with base pair opening. Asynchronous release of nascent nucleotides rationalizes various observations of its dsNA unwinding and may be used to coordinate the translocation speed of NS3 along the RNA during viral replication.

Seven-year neurodevelopmental scores and prenatal exposure to chlorpyrifos, a common agricultural pesticide.

BACKGROUND: In a longitudinal birth cohort study of inner-city mothers and children (Columbia Center for Children's Environmental Health), we have previously reported that prenatal exposure to chlorpyrifos (CPF) was associated with neurodevelopmental problems at 3 years of age. OBJECTIVE: The goal of the study was to estimate the relationship between prenatal CPF exposure and neurodevelopment among cohort children at 7 years of age. METHODS: In a sample of 265 children, participants in a prospective study of air pollution, we measured prenatal CPF exposure using umbilical cord blood plasma (picograms/gram plasma) and 7-year neurodevelopment using the Wechsler Intelligence Scale for Children, 4th edition (WISC-IV). Linear regression models were used to estimate associations, with covariate selection based on two alternate approaches. RESULTS: On average, for each standard deviation increase in CPF exposure (4.61 pg/g), Full-Scale intelligence quotient (IQ) declined by 1.4% and Working Memory declined by 2.8%. Final covariates included maternal educational level, maternal IQ, and quality of the home environment. We found no significant interactions between CPF and any covariates, including the other chemical exposures measured during the prenatal period (environmental tobacco smoke and polycyclic aromatic hydrocarbons). CONCLUSIONS: We report evidence of deficits in Working Memory Index and Full-Scale IQ as a function of prenatal CPF exposure at 7 years of age. These findings are important in light of continued widespread use of CPF in agricultural settings and possible longer-term educational implications of early cognitive deficits.

The effect of antihypertensive class on intraoperative pressor requirements during carotid endarterectomy.

BACKGROUND: Certain classes of antihypertensive drugs have been associated with intraoperative hypotension, and frequently, patients are receiving multiple classes of antihypertensive medications. We sought to determine whether one class of antihypertensive medication either alone, or in combination with other classes of antihypertensive medications, increased the probability of intraoperative hypotension, determined by the amount of vasopressor required during carotid endarterectomy (CEA) performed under general anesthesia with specific arterial blood pressure management. METHODS: This is a post hoc analysis of 252 patients scheduled for elective CEA under general anesthesia, all of whom participated in a prospective evaluation of cognitive dysfunction. Patients were characterized by class and number of preoperative antihypertensive medications taken. A predetermined anesthetic regimen was administered to all patients, with a phenylephrine infusion titrated to maintain mean arterial blood pressure at baseline before clamping the carotid artery, and approximately 20% above baseline during clamping. Computerized anesthesia records were used to record hemodynamics and to quantify medication administered intraoperatively. RESULTS: Patients taking diuretics as part of their antihypertensive regimen required significantly more (1.6 times) total intraoperative phenylephrine than those not taking diuretics, independently of the number of other antihypertensive medications. This difference in the phenylephrine requirement occurs only during the preclamp period, i.e., from induction to application of carotid artery clamping for the maintenance of preoperative blood pressure. However, in contrast to this result, there is no difference in pressor requirement comparing classes of antihypertensive medications to increase the mean arterial blood pressure 20% above baseline during the period when the carotid artery is clamped. CONCLUSION: Diuretics are associated with increased vasopressor requirements in patients having a CEA under general anesthesia in the preclamp period, which is likely true for any patient having a general anesthetic.

A nonlinear model for highly unbalanced repeated time-to-event data: Application to labor progression.

The collection of repeated measurements over time on an experimental unit to study the changes over time of a certain characteristic is common in biological and clinical studies. Data of this type are also often referred to as growth curve data or repeated measures data. There arise situations when one is interested in an estimate of the time to an event, based on a characteristic that indicates progression towards the event. The assessment of the progression of labor during childbirth based on cervical dilation is one such example. Here increase in the dilation of the cervix indicates progression towards delivery. Based on how long one has been in labor and an estimate of the time to complete dilation one might make crucial decisions like the decision to administer a drug or to perform a C-section. Here a repeated measures approach is developed to model the time to the event. The parameters of the model are estimated by a maximum likelihood approach. A general model is developed for a class of data structures and a nonlinear model is developed specific to the labor progression data. Simulations are performed to assess the methodology and conditions are suggested for predicting the time to an event.

The relationship between glycosylated hemoglobin and perioperative glucose control in patients with diabetes.

PURPOSE: Hyperglycemia and elevated glycosylated hemoglobin (HbA(1c)) are associated with perioperative morbidity in patients with diabetes, but the relationship between long-term glycemic control and perioperative glucose control is unknown. The purpose of this study was to determine the relationship between glycosylated hemoglobin (HbA(1c)) and perioperative glucose in fasting patients with type 2 diabetes undergoing elective non-cardiac surgery. METHODS: This was a prospective observational study of 244 adult patients with type 2 diabetes who were evaluated before elective non-cardiac surgery at a preoperative medicine clinic in a tertiary care medical centre during the period September 2004 to May 2005. Preoperative HbA(1c) levels were determined, and preoperative and postoperative glucose values were measured on the day of surgery. The primary outcome variables were preoperative and postoperative blood glucose values. RESULTS: Half of all study patients had an HbA(1c) > or = 7%, including 23% of patients with HbA(1c) >/= 8%. HbA(1c) levels predict preoperative glucose levels, and preoperative glucose levels and duration of surgery predict postoperative glucose levels. Glucose levels in one-third of the patients with type 2 diabetes decreased during surgery without administration of insulin or glucose-regulating medications. CONCLUSION: HbA(1c) values may serve as biomarkers for glucose control during the immediate perioperative period in patients with type 2 diabetes undergoing elective surgery.

Quadratic System Identification: a statistical framework for the paired-pulse paradigm.

System Identification refers to the problem of identifying a model or description of a system based on a stretch of input and the corresponding output from the system. The paired-pulse paradigm or the conditioning test pulse paradigm is often used in neurophysiology experiments. In this work we provide a statistical framework for the conditioning test pulse paradigm which also serves as a system identification tool for quadratic or second order Volterra systems. A nonparametric spectral domain based methodology is proposed for the quadratic system identification. It is shown that by carrying out the analysis in the spectral domain one needs to perform only a single set of double pulse experiments as opposed to multiple sets of experiments in the time domain. Simulation studies are performed to assess the performance of the methodology and to study the conditions under which the methods are expected to perform well.

RNA unwinding by NS3 helicase: a statistical approach.

The study of double-stranded RNA unwinding by helicases is a problem of basic scientific interest. One such example is provided by studies on the hepatitis C virus (HCV) NS3 helicase using single molecule mechanical experiments. HCV currently infects nearly 3% of the world population and NS3 is a protein essential for viral genome replication. The objective of this study is to model the RNA unwinding mechanism based on previously published data and study its characteristics and their dependence on force, ATP and NS3 protein concentration. In this work, RNA unwinding by NS3 helicase is hypothesized to occur in a series of discrete steps and the steps themselves occurring in accordance with an underlying point process. A point process driven change point model is employed to model the RNA unwinding mechanism. The results are in large agreement with findings in previous studies. A gamma distribution based renewal process was found to model well the point process that drives the unwinding mechanism. The analysis suggests that the periods of constant extension observed during NS3 activity can indeed be classified into pauses and subpauses and that each depend on the ATP concentration. The step size is independent of external factors and seems to have a median value of 11.37 base pairs. The steps themselves are composed of a number of substeps with an average of about 4 substeps per step and an average substep size of about 3.7 base pairs. An interesting finding pertains to the stepping velocity. Our analysis indicates that stepping velocity may be of two kinds- a low and a high velocity.

A point process driven multiple change point model: a robust resistant approach.

Helicases are a class of enzymes involved in Ribonucleic Acid (RNA) metabolism. In this work a statistical method is proposed to analyze the individual mechanistic cycle of these motor proteins which are crucial to the understanding of their cellular functions. The RNA unwinding by NS3 helicase is hypothesized to occur in a series of discrete steps and the steps themselves occurring in accordance to an underlying point process. A point process driven multiple change point model is proposed to model the RNA unwinding mechanism. The methods are portable to other areas of applications as well. Algorithms based on robust-resistant statistical procedures are proposed to detect the change points. Both sequential and a posteriori change point models are considered. The relevant parameters of interest are estimated using a maximum likelihood approach. Simulations are performed to assess the performance of the methodology.