Using Alzheimer's disease blood tests to accelerate clinical trial enrollment.

INTRODUCTION: Screening potential participants in Alzheimer's disease (AD) clinical trials with amyloid positron emission tomography (PET) is often time consuming and expensive. METHODS: A web-based application was developed to model the time and financial cost of screening for AD clinical trials. Four screening approaches were compared; three approaches included an AD blood test at different stages of the screening process. RESULTS: The traditional screening approach using only amyloid PET was the most time consuming and expensive. Incorporating an AD blood test at any point in the screening process decreased both the time and financial cost of trial enrollment. Improvements in AD blood test accuracy over currently available tests only marginally increased savings. Use of a high specificity cut-off may improve the feasibility of screening with only an AD blood test. DISCUSSION: Incorporating AD blood tests into screening for AD clinical trials may reduce the time and financial cost of enrollment. HIGHLIGHTS: The time and cost of enrolling participants in Alzheimer's disease (AD) clinical trials were modeled. A web-based application was developed to enable evaluation of key parameters. AD blood tests may decrease the time and financial cost of clinical trial enrollment. Improvements in AD blood test accuracy only marginally increased savings. Use of a high specificity cut-off may enable screening with only an AD blood test.

Making Meaningful Use of Price Transparency Data: Describing Price Variation of Spine Surgery and Imaging in a Single System.

Price transparency is an increasingly popular solution for high healthcare expenditures in the United States, but little is known about its potential to facilitate patient price shopping. Our objective was to analyze interhospital and interpayer price variability in spine surgery and spine imaging using newly public payer-specific negotiated charges (PNCs). We selected a subset of billing codes for spine surgery and spine imaging at 12 hospitals within a Saint Louis metropolitan area healthcare system. We then compared PNCs for these procedures and tested for significant differences in interhospital and interinsurer IQR using the Mann-Whitney U Test. We found significantly greater IQRs of PNCs as a factor of the insurance plan than as a factor of the hospital for cervical spinal fusions (interinsurer IQR $8256; interhospital IQR $533; P < .0001), noncervical spinal fusions (interinsurer IQR $28 423; interhospital IQR $5512; P < .001), computed tomographies of the lower spine (interinsurer IQR $595; interhospital IQR $113; P < .0001), and MRIs lower spinal canal (interinsurer IQR $1010; interhospital IQR $158; P < .0001). There was no significant difference between the interinsurer IQR and the interhospital IQR for lower spine x-rays (interinsurer IQR $107; interhospital IQR $67; P = .0543). Despite some between-hospital heterogeneity, we show significantly higher price variability between insurers than between hospitals. Our single system analysis limits our ability to generalize, but our results suggest that savings depend more on hospital and provider negotiations than patient price shopping, given the difficulty of switching insurers.

Caregiver-reported executive functioning and associated adaptive and challenging behaviour in children with histories of developmental delay.

BACKGROUND: Deficits in executive functioning (EF) have been measured in individuals with developmental disabilities, such as autism spectrum disorder and attention-deficit/hyperactivity disorder, through the use of behaviour rating scales and performance-based assessment. Associations between EF and variables such as challenging and adaptive behaviour have been observed; however, limited research exists on EF profiles in children with heterogeneous developmental delay or with intellectual disability (ID) or the impact of EF on adaptive and challenging behaviour with this population. METHODS: The present study sought to examine the EF profile of 93 children (75 male and 18 female) previously identified with developmental delay in early childhood. EF was assessed using the Behaviour Rating Inventory of Executive Function, Second Edition (BRIEF-2). Children were categorised into an ID group (n = 14) or no ID group (n = 79) based on scores from cognitive and adaptive behaviour assessments. EF profiles were investigated and compared by group. In addition, the impact of EF on both adaptive behaviour and challenging behaviour was measured using hierarchical linear regressions. RESULTS: Statistically significant differences in caregiver-reported EF were not observed between groups; however, both the ID and the no ID group scores were elevated as reported by their caregivers. For the overall sample, caregiver-EF accounted for significant variance in both adaptive (22%) and challenging (68%) behaviour after accounting for child age and sex. CONCLUSIONS: Results indicated deficits in EF for children with and without ID. The significance of EF was accounted for in both adaptive and challenging behaviour for all children in the sample. Future research could elucidate the role of adaptive and challenging behaviour in understanding EF variability among children with histories of developmental delay.

Health, Human Capital and Domestic Violence.

We treat health as a form of human capital and hypothesize that women with more human capital face stronger incentives to make costly investments with future payoffs, such as avoiding abusive partners and reducing drug use. To test this hypothesis, we exploit the unanticipated introduction of an HIV treatment, HAART, which dramatically improved HIV+ women's health. We find that after the introduction of HAART HIV+ women who experienced increases in expected longevity exhibited a decrease in domestic violence of 15% and in drug use of 1520%. We rule out confounding via secular trends using a control group of healthier women.

The feasibility and accuracy of ultrasound assessment in the labor room.

Objective: Vaginal examination is widely used to assess the progress of labor; however, it is subjective and poorly reproducible. We aim to assess the feasibility and accuracy of transabdominal and transperineal ultrasound compared to vaginal examination in the assessment of labor and its progress. Methods: Women were recruited as they presented for assessment of labor to a tertiary inner city maternity service. Paired vaginal and ultrasound assessments were performed in 192 women at 24-42 weeks. Fetal head position was assessed by transabdominal ultrasound defined in relation to the occiput position transformed to a 12-hour clock face; fetal head station defined as head-perineum distance by transperineal ultrasound; cervical dilatation by anterior to posterior cervical rim measurement and caput succedaneum by skin-skull distance on transperineal ultrasound. Results: Fetal head position was recorded in 99.7% (298/299) of US and 51.5% (154/299) on vaginal examination (p < .0001 1 ). Bland-Altman analysis showed 95% limits of agreement, -5.31 to 4.84 clock hours. Head station was recorded in 96.3% (308/320) on vaginal examination (VE) and 95.9% (307/320) on US (p = .79 1 ). Head station and head perineum distance were negatively correlated (Spearman's r = -.57, p < .0001). 54.4% (178/327) of cervical dilatation measurements were determined using US and 100% on VE/speculum (p < .0001). Bland-Altman analysis showed 95% limits of agreement -2.51-2.16 cm. The presence of caput could be assessed in 98.4% (315/320) of US and was commented in 95.3% (305/320) of VEs, with agreement for the presence of caput of 76% (p < .05). Fetuses with caput greater than 10 mm had significantly lower head station (p < .0001). Conclusions: We describe comprehensive ultrasound assessments in the labor room that could be translated to the assessment of women in labor. Fetal head position is unreliably determined by vaginal examination and agrees poorly with US. Head perineum distance has a moderate correlation with fetal head station in relation to the ischial spines based on vaginal examination. Cervical dilatation is not reliably assessed by ultrasound except at dilatations of less than 4 cm. Caput is readily quantifiable by ultrasound and its presence is associated with lower fetal head station. Transabdominal and transperineal ultrasound is feasible in the labor room with an accuracy that is generally greater than vaginal examinations.

Health Care Access, Costs, and Treatment Dynamics: Evidence from In Vitro Fertilization.

We study public policies designed to improve access and reduce costs for in vitro fertilization (IVF). High out-of-pocket prices can deter potential patients from IVF, while active patients have an incentive to risk costly high-order pregnancies to improve their odds of treatment success. We analyze IVF's rich choice structure by estimating a dynamic model of patients' choices within and across treatments. Policy simulations show that insurance mandates for treatment or hard limits on treatment aggressiveness can improve access or costs, but not both. Insurance plus price-based incentives against risky treatment, however, can together improve patient welfare and reduce medical costs.

"It's all in the history": A service evaluation of the quality of radiological requests in acute imaging.

INTRODUCTION: The aim of this service evaluation project was to assess the quality of clinical details provided in radiological requests. METHODS: A retrospective review of adult inpatient and emergency department radiological requests over a seven-day period was performed, using the local Clinical Radiological Information System (CRIS). Requests for plain film, CT, MRI and Ultrasound were assessed for the inclusion of a clinical question, lateralisation/localisation of signs or symptoms if required, and relevant past medical/surgical history if available. RESULTS: 1548 imaging requests were analysed. 76% asked a specific clinical question. 74% of requests requiring localisation provided this. Of those cases with relevant past medical or surgical history available, 49% mentioned this. Emergency department (ED) requests provided localisation when required in 81% of cases compared to 62% of in-patients (p < 0.05). However, in-patient requests contained relevant past history in 53% of cases compared to 40% for ED requests (p = 0.00096). Compared to plain film requests, those for CT, MRI and Ultrasound studies were more complete in respect to inclusion of a clinical question (88% versus 72%, p < 0.05), localisation if required (83% versus 71%, p = 0.0007) and pertinent clinical history (67% versus 42%, p < 0.05). Requests from the weekend more often included a clinical question (83% vs 75%, p = 0.00054) and localisation if needed (84% vs 71%, p = 0.00188) compared with weekday requests. CONCLUSION: This large-scale service evaluation project shows that the quality of clinical details in requests for radiological investigations requires improvement, particularly in regard to inclusion of relevant past medical and surgical history.

A high-density SNP chip for genotyping great tit (Parus major) populations and its application to studying the genetic architecture of exploration behaviour.

High-density SNP microarrays ("SNP chips") are a rapid, accurate and efficient method for genotyping several hundred thousand polymorphisms in large numbers of individuals. While SNP chips are routinely used in human genetics and in animal and plant breeding, they are less widely used in evolutionary and ecological research. In this article, we describe the development and application of a high-density Affymetrix Axiom chip with around 500,000 SNPs, designed to perform genomics studies of great tit (Parus major) populations. We demonstrate that the per-SNP genotype error rate is well below 1% and that the chip can also be used to identify structural or copy number variation. The chip is used to explore the genetic architecture of exploration behaviour (EB), a personality trait that has been widely studied in great tits and other species. No SNPs reached genomewide significance, including at DRD4, a candidate gene. However, EB is heritable and appears to have a polygenic architecture. Researchers developing similar SNP chips may note: (i) SNPs previously typed on alternative platforms are more likely to be converted to working assays; (ii) detecting SNPs by more than one pipeline, and in independent data sets, ensures a high proportion of working assays; (iii) allele frequency ascertainment bias is minimized by performing SNP discovery in individuals from multiple populations; and (iv) samples with the lowest call rates tend to also have the greatest genotyping error rates.

A Translational Systems Pharmacology Model for Aß Kinetics in Mouse, Monkey, and Human.

A mechanistic model of amyloid beta production, degradation, and distribution was constructed for mouse, monkey, and human, calibrated and externally verified across multiple datasets. Simulations of single-dose avagacestat treatment demonstrate that the Aß42 brain inhibition may exceed that in cerebrospinal fluid (CSF). The dose that achieves 50% CSF Aß40 inhibition for humans (both healthy and with Alzheimer's disease (AD)) is about 1 mpk, one order of magnitude lower than for mouse (10 mpk), mainly because of differences in pharmacokinetics. The predicted maximal percent of brain Aß42 inhibition after single-dose avagacestat is higher for AD subjects (about 60%) than for healthy individuals (about 45%). The probability of achieving a normal physiological level for Aß42 in brain (1 nM) during multiple avagacestat dosing can be increased by using a dosing regimen that achieves higher exposure. The proposed model allows prediction of brain pharmacodynamics for different species given differing dosing regimens.

Use of Quantile Regression to Determine the Impact on Total Health Care Costs of Surgical Site Infections Following Common Ambulatory Procedures.

OBJECTIVE: To determine the impact of surgical site infections (SSIs) on health care costs following common ambulatory surgical procedures throughout the cost distribution. BACKGROUND: Data on costs of SSIs following ambulatory surgery are sparse, particularly variation beyond just mean costs. METHODS: We performed a retrospective cohort study of persons undergoing cholecystectomy, breast-conserving surgery, anterior cruciate ligament reconstruction, and hernia repair from December 31, 2004 to December 31, 2010 using commercial insurer claims data. SSIs within 90 days post-procedure were identified; infections during a hospitalization or requiring surgery were considered serious. We used quantile regression, controlling for patient, operative, and postoperative factors to examine the impact of SSIs on 180-day health care costs throughout the cost distribution. RESULTS: The incidence of serious and nonserious SSIs was 0.8% and 0.2%, respectively, after 21,062 anterior cruciate ligament reconstruction, 0.5% and 0.3% after 57,750 cholecystectomy, 0.6% and 0.5% after 60,681 hernia, and 0.8% and 0.8% after 42,489 breast-conserving surgery procedures. Serious SSIs were associated with significantly higher costs than nonserious SSIs for all 4 procedures throughout the cost distribution. The attributable cost of serious SSIs increased for both cholecystectomy and hernia repair as the quantile of total costs increased ($38,410 for cholecystectomy with serious SSI vs no SSI at the 70th percentile of costs, up to $89,371 at the 90th percentile). CONCLUSIONS: SSIs, particularly serious infections resulting in hospitalization or surgical treatment, were associated with significantly increased health care costs after 4 common surgical procedures. Quantile regression illustrated the differential effect of serious SSIs on health care costs at the upper end of the cost distribution.

Mechanistic Projection of First-in-Human Dose for Bispecific Immunomodulatory P-Cadherin LP-DART: An Integrated PK/PD Modeling Approach.

A bispecific immunomodulatory biotherapeutic molecule (P-cadherin LP-DART) based on the Dual Affinity Re-Targeting (DART) scaffold has been developed as a potential antitumor treatment showing efficacy in preclinical testing. A minimal anticipated biological effect level (MABEL) approach was applied to project the first-in-human (FIH) dose, because of its immune agonistic properties following target engagement. The pharmacological activity of P-cadherin LP-DART is driven by binding to both P-cadherin on the tumor cells and CD3 on T cells. Therefore, the concentration of the tri-molecular synapse formed between drug, T cell, and tumor cell, rather than drug concentration, is responsible for efficacy. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD)-driven approach was explored to understand the exposure-response relationship based on the synapse concentration to project the MABEL dose. Orthogonal approaches including PK-driven and receptor occupancy calculations were also investigated. This study showcases the application of PK/PD modeling in immune-oncology, and could potentially be implemented for other bispecific biotherapeutics.

Barriers to Innovation in Urban Wastewater Utilities: Attitudes of Managers in California.

In many regions of the world, urban water systems will need to transition into fundamentally different forms to address current stressors and meet impending challenges-faster innovation will need to be part of these transitions. To assess the innovation deficit in urban water organizations and to identify means for supporting innovation, we surveyed wastewater utility managers in California. Our results reveal insights about the attitudes towards innovation among decision makers, and how perceptions at the level of individual managers might create disincentives for experimentation. Although managers reported feeling relatively unhindered organizationally, they also spend less time on innovation than they feel they should. The most frequently reported barriers to innovation included cost and financing; risk and risk aversion; and regulatory compliance. Considering these results in the context of prior research on innovation systems, we conclude that collective action may be required to address underinvestment in innovation.

Profiling Individual Surgeon Performance Using Information from a High-Quality Clinical Registry: Opportunities and Limitations.

BACKGROUND: There is increasing interest in profiling the quality of individual medical providers. Valid assessment of individuals should highlight improvement opportunities, but must be considered in the context of limitations. STUDY DESIGN: High quality clinical data from the American College of Surgeons NSQIP, gathered in accordance with strict policies and specifications, was used to construct individual surgeon-level assessments. There were 39,976 cases evaluated, performed by 197 surgeons across 9 hospitals. Both 2-level (cases by surgeon) and 3-level (cases by surgeon by hospital) risk-adjusted, hierarchical regression analyses were performed. Outcomes were 30-day postoperative morbidity, surgical site infection, and mortality. Surgeon performance was compared in both absolute and relative terms. "Signal-to-noise" reliability was calculated for surgeons and models. Projected case requirements for reliability levels were generated. RESULTS: Surgeon performances could be distinguished to different degrees: morbidity distinguished best, mortality least. Outliers could be identified for morbidity and infection, but not mortality. Reliability was also highest for morbidity and lowest for mortality. Even models with high overall reliability did not assess all providers reliably. Incorporating institutional effects had predictable effects: penalizing providers at "good" institutions, benefiting providers at "poor" institutions. CONCLUSIONS: Individual surgeon profiles can, at times, be distinguished with moderate or good reliability, but to different degrees in different models. Absolute and relative comparisons are feasible. Incorporating institutional level effects in individual provider modeling presents an interesting policy dilemma, appearing to benefit providers at "poor-performing" institutions, but penalizing those at "high-performing" ones. No portrayal of individual medical provider quality should be accepted without consideration of modeling rationale and, critically, reliability.

A Mechanistic Pharmacokinetic Model for Liver Transporter Substrates Under Liver Cirrhosis Conditions.

Liver cirrhosis is a disease characterized by the loss of functional liver mass. Physiologically based pharmacokinetic (PBPK) modeling was applied to interpret and predict how the interplay among physiological changes in cirrhosis affects pharmacokinetics. However, previous PBPK models under cirrhotic conditions were developed for permeable cytochrome P450 substrates and do not directly apply to substrates of liver transporters. This study characterizes a PBPK model for liver transporter substrates in relation to the severity of liver cirrhosis. A published PBPK model structure for liver transporter substrates under healthy conditions and the physiological changes for cirrhosis are combined to simulate pharmacokinetics of liver transporter substrates in patients with mild and moderate cirrhosis. The simulated pharmacokinetics under liver cirrhosis reasonably approximate observations. This analysis includes meta-analysis to obtain system-dependent parameters in cirrhosis patients and a top-down approach to improve understanding of the effect of cirrhosis on transporter-mediated drug disposition under cirrhotic conditions.

Blood pressure and arterial stiffness in patients with high sodium intake in relation to sodium handling and left ventricular diastolic dysfunction status.

In a population with high sodium consumption, we assessed relation between brachial and central blood pressures, elastic properties of large arteries, echocardiographic left ventricular diastolic function and sodium reabsorption as fractional urinary lithium excretion in proximal (FELi) and fractional sodium reabsorption in distal tubules assessed using the endogenous lithium clearance. Mean±s.d. age of 131 treated hypertensive patients (66 men and 65 women) was 61.9±7.5 years. We found significant interaction between left ventricular diastolic function and FELi with respect to the values of brachial blood pressure: systolic (SBP), diastolic (DBP) and mean blood pressure (MBP) (all PINT<0.03). In patients with FELi below the median value and impaired left ventricular diastolic function, the values of SBP (149.3 vs 132.5 mm Hg; P=0.005), DBP (85.1 vs 76.1 mm Hg; P=0.001), MBP (106.5 vs 94.9 mm Hg; P=0.001), central SBP (SBPC) (137.4 vs 122.0 mm Hg; P=0.01), central DBP (DBPC) (84.8 vs 76.0 mm Hg; P=0.003), central MBP (MBPC) (106.9 vs 95.9 mm Hg; P=0.007), aortic pulse wave augmentation (18.0 vs 13.5 mm Hg; P=0.03), pulse wave velocity (14.6 vs 12.5 m s(-1); P=0.02) and central aortic pulse wave augmentation index (155.7% vs 140.9%; P=0.01) were significantly higher than in patients with normal left ventricular diastolic function. Such relationships were not observed in the entire group and patients with FELi above the median value. In the hypertensive population with high sodium intake, increased sodium reabsorption in proximal tubules may affect blood pressure parameters and arterial wall damage, thus contributing to the development of left ventricular diastolic function impairment.

Toward Prospective Prediction of Pharmacokinetics in OATP1B1 Genetic Variant Populations.

Physiologically based pharmacokinetic (PBPK) models are increasingly being used to provide human pharmacokinetic (PK) predictions for organic anion-transporting polypeptide (OATP) substrates based on in vitro assay data. As a natural extension in the application of these models, in this study, we incorporated in vitro information of three major OATP1B1 genetic variants into a previously reported PBPK model to predict the impact of OATP1B1 polymorphisms on human PK. Using pravastatin and rosuvastatin as examples, we showed that the predicted plasma concentration-time profiles in groups carrying different OATP1B1 genetic variants reasonably matched the clinical observations from multiple studies. This modeling and simulation approach may aid decision making in early pharmaceutical research and development as well as patient-specific dose adjustment in clinical practice.