U.S. payer budget impact of using an AI-augmented cancer risk discrimination digital histopathology platform to identify high-risk of recurrence in women with early-stage invasive breast cancer.

Aims: Use of gene expression signatures to predict adjuvant chemotherapy benefit in women with early-stage breast cancer is increasing. However, high cost, limited access, and eligibility for these tests results in the adoption of less precise assessment approaches. This study evaluates the cost impact of PreciseDx Breast (PDxBr), an AI-augmented histopathology platform that assesses the 6-year risk of recurrence in early-stage invasive breast cancer patients to help improve informed use of adjuvant chemotherapy.Materials and Methods: A decision-tree Markov model was developed to compare the costs of treatment guided by standard of care (SOC) risk assessment (i.e., clinical diagnostic workup with or without Oncotype DX) versus PDxBr with SOC in a hypothetical cohort of U.S. women with early-stage invasive breast cancer. A commercial payer perspective compares costs of testing, adjuvant therapy, recurrence, adverse events, surveillance, and end-of-life care.Results: PDxBr use in prognostic evaluation resulted in savings of $4 million (M) in year one compared to current SOC in 1M females members. Over 6-years, savings increased to $12.5M. The per-treated patient costs in year one amounted to $19.5 thousand (K) for SOC and $16.9K for PDxBr.Limitations: For simplicity, recurrence was not specified. We performed scenario analyses to account for variations in rates for local, regional, and distant recurrence. Second, a recurrent patient incurs the total cost of treated recurrence in the first year and goes back to remission or death. Third, CDK4/6i treatment is only incorporated in the recurrence costs but not in the first line of treatment for early-stage breast cancer due to limited data.Conclusions: Sensitivity analyses demonstrated robust overall savings to changes in all variables in the model. The use of PDxBr to assess breast cancer recurrence risk has the potential to fill gaps in care and reduce costs when gene expression signatures are not available.

Cost-effectiveness of home non-invasive ventilation in patients with persistent hypercapnia after an acute exacerbation of COPD in the UK.

Home non-invasive mechanical ventilation (HMV) with home oxygen therapy (HOT) in patients with persistent hypercapnia following an acute exacerbation of chronic obstructive pulmonary disease delays hospital readmission. The economic impact of this treatment is unknown. We evaluated the cost-effectiveness of HMV in the UK healthcare system using data from a previously published efficacy trial. Quality-adjusted life-years (QALYs) were computed from EQ-5D-5L. Accounting for all direct patient costs HOT-HMV was £512 (95%CI £36 to £990) more expensive per patient per year than HOT-alone. This small increase in cost was accompanied by increased quality of life leading to an incremental cost-effectiveness ratio of £10 259 per QALY. HOT-HMV was cost-effective in this clinical population. Trial registration number: NCT00990132.

Efficacy and Safety of a Nonanimal Stabilized Hyaluronic Acid/Dextranomer in Improving Fecal Incontinence: A Prospective, Single-Arm, Multicenter, Clinical Study With 36-Month Follow-up.

BACKGROUND: Fecal incontinence affects 7% to 12% of the US adult population, causing social, financial, and quality of life burdens. OBJECTIVE: The primary aim of this study was to evaluate the efficacy and safety of nonanimal stabilized hyaluronic acid/dextranomer through 36 months as a condition of postmarket approval application. DESIGN: This was a prospective, single-arm, multicenter, observational Food and Drug Administration-mandated postapproval clinical study. SETTINGS: This study was designed and executed by participating centers in 18 hospitals and colorectal health clinics in coordination with the Food and Drug Administration and the study sponsor. PATIENTS: A total of 283 subjects who previously failed conservative therapy were enrolled across 18 US sites. INTERVENTIONS: Participants received 1 to 2 nonanimal stabilized hyaluronic acid/dextranomer treatments. The first treatment occurred within 30 days of baseline, and a second treatment was administered 1 to 3 months after initial treatment if determined necessary by the physician. Subjects were followed through 7 visits over 36 months after last treatment. MAIN OUTCOME MEASURES: Efficacy (as specified by the Food and Drug Administration) was measured as a fecal incontinence reintervention rate of <50% at 36 months. Reintervention included nonanimal stabilized hyaluronic acid/dextranomer re-treatment, surgical interventions, and physical therapy. Safety was measured by device-related adverse events. Secondary end points included Fecal Incontinence Quality of Life Scale and Cleveland Clinic Florida Fecal Incontinence Score. RESULTS: Using a Bayesian estimate, the reintervention rate of the intention-to-treat population (n = 283) was 18.9% (95% CI, 14.0-24.4) at 36 months. At 36 months, the reintervention rate for subjects with complete data (n = 192) was 20.8% (95% CI, 15.1-26.6). Significant improvement ( p < 0.0001) was noted across the Cleveland Clinic Florida Fecal Incontinence Score and Fecal Incontinence Quality of Life subscales at 36 months. Ninety-two device-related adverse events were reported by 15.2% of enrolled patients; most were GI disorders and resolved quickly. There were no serious adverse events. LIMITATIONS: Limitations of the study included a 32% attrition rate and homogeneous patient population (91.8% white; 85.5% female), possibly limiting generalizability. CONCLUSIONS: Nonanimal stabilized hyaluronic acid/dextranomer demonstrated clinically significant, sustained improvement in symptoms and quality of life for fecal incontinence patients without the occurrence of any serious adverse events. See Video Abstract at http://links.lww.com/DCR/B890 . REGISTRATION: ClinicalTrials.gov ; Unique identifier: NCT01647906. EFICACIA Y SEGURIDAD DE UN CIDO HIALURNICO/ DEXTRANMERO ESTABILIZADO DE ORGEN NO ANIMAL PARA MEJORAR LA INCONTINENCIA FECAL UN ESTUDIO CLNICO PROSPECTIVO, MULTICNTRICO Y DE UN SOLO BRAZO CON SEGUIMIENTO DE MESES: ANTECEDENTES:La incontinencia fecal afecta entre el 7 y el 12% de la población adulta de los EE. UU. Y genera cargas sociales, económicas y de calidad de vida.OBJETIVO:Los objetivos principales de este estudio fueron evaluar la eficacia y seguridad del ácido hialurónico/ dextranómero estabilizado de origen no animal durante 36 meses como condición para la solicitud de aprobación posterior a la comercialización.DISEÑO:Este fue un estudio clínico prospectivo, observacional, de un solo brazo, multicéntrico, ordenado por la FDA después de la aprobación.AJUSTES:Este estudio fue diseñado por los investigadores participantes, la FDA y el patrocinador del estudio que gestionó la recopilación de datos.PACIENTES:Un total de 283 sujetos en quienes previamente falló la terapia conservadora se inscribieron en el estudio prospectivo de un solo brazo en 18 sedes de EE. UU. (NCT01647906).INTERVENCIONES:Los participantes recibieron 1-2 tratamientos con ácido hialurónico/ dextranómero estabilizado no animal. El primer tratamiento se dio dentro de los 30 días posteriores al inicio, mientras que un segundo tratamiento se administró 1-3 meses después del tratamiento inicial si el médico lo determinaba necesario. Los sujetos fueron seguidos durante 7 visitas durante 36 meses después del último tratamiento.PRINCIPALES MEDIDAS DE RESULTADO:La eficacia (según especificado por la FDA) se midió como una tasa de reintervención de incontinencia fecal de <50% a los 36 meses. La reintervención incluyó retratamiento con ácido hialurónico/ dextranómero estabilizado no animal, intervenciones quirúrgicas y fisioterapia. La seguridad se midió mediante los eventos adversos relacionados con tratamiento. Los criterios de valoración secundarios incluyeron la escala de calidad de vida de incontinencia fecal y la puntuación de incontinencia fecal de Cleveland Clinic Florida.RESULTADOS:Utilizando una estimación bayesiana, la tasa de reintervención de la población por intención de tratar (n = 283) fue del 18.9% (IC del 95%: 14.0%, 24.4%) a los 36 meses. A los 36 meses, la tasa de reintervención para los sujetos con datos completos (n = 192) fue del 20.8% (IC del 95%: 15.1%, 26.6%). Se observó una mejora significativa (p <0.0001) en las subescalas de la puntuación de incontinencia fecal de la Cleveland Clinic Florida y de la calidad de vida de la incontinencia fecal a los 36 meses. El 15.2% de los pacientes inscritos informaron 92 eventos adversos relacionados con el tratmiento; la mayoría eran trastornos gastrointestinales y se resolvieron rápidamente. No hubo eventos adversos graves.LIMITACIONES:Las limitaciones incluyen una tasa de deserción del 32% y una población de pacientes homogénea (91.8% blancos, 85.5% mujeres), lo que posiblemente limite la generalización.CONCLUSIÓNES:El ácido hialurónico/ dextranómero estabilizado de origen no animal demostró una mejora sostenida y clínicamente significativa de los síntomas y la calidad de vida de los pacientes con incontinencia fecal, sin que se produjeran efectos adversos graves. Consulte el Video Resumen en http://links.lww.com/DCR/B890 . ( Traducción-Dr. Jorge Silva Velazco )Registro: ClinicalTrials.gov número NCT01647906.

A kidney diagnostic's impact on physician decision-making in diabetic kidney disease.

OBJECTIVES: Estimated glomerular filtration rate (eGFR) and albuminuria, the current standard-of-care tests that predict risk of kidney function decline in early-stage diabetic kidney disease (DKD), are only modestly useful. We evaluated the decision-making impact of an artificial intelligence-enabled prognostic test, KidneyIntelX, in the management of DKD by primary care physicians (PCPs). STUDY DESIGN: This was a prospective web-based survey administered among PCPs in the United States. METHODS: We used conjoint analysis with multivariable logit models to estimate PCP preferences. The survey included hypothetical patient profiles with 6 attributes: albuminuria, eGFR, age, blood pressure (BP), hemoglobin A1c (HbA1c), and KidneyIntelX result. Each PCP viewed 8 patient profiles randomly selected from 42 unique profiles having 1 level from each attribute. For each patient, PCPs were asked to indicate whether they would prescribe a sodium-glucose cotransporter-2 (SGLT2) inhibitor, increase angiotensin receptor blocker (ARB) dose, and/or refer to a nephrologist. RESULTS: A total of 401 PCPs completed the survey (response rate, 8.8%). The relative importance of the top 2 attributes for each decision were HbA1c (52%) and KidneyIntelX result (23%) for prescribing SGLT2 inhibitors, BP (62%) and KidneyIntelX result (13%) for increasing ARB dose, and eGFR (42%) and KidneyIntelX result (27%) for nephrologist referral. A high-risk KidneyIntelX result was associated with significantly higher odds of PCPs prescribing SGLT2 inhibitors (odds ratio [OR], 1.64; 95% CI, 1.29-2.08), increasing ARB dose (OR, 1.49; 95% CI, 1.17-1.89), and referring to a nephrologist (OR, 2.47; 95% CI, 1.99-3.08) compared with no test. CONCLUSIONS: The KidneyIntelX test had greater relative importance than albuminuria and eGFR to PCPs in making treatment decisions and was second only to eGFR for nephrologist referrals. Because of its significant impact on decision-making, KidneyIntelX has high clinical utility in DKD management.

Healthcare resource use and cost burden of urinary incontinence to United States payers.

OBJECTIVE: To assess healthcare resource utilization and costs for female patients diagnosed with stress or mixed urinary incontinence (SUI/MUI) compared to a matched cohort of patients without SUI/MUI. METHODS: We conducted a retrospective matched cohort study of women using the IBM MarketScan research database. Women diagnosed with SUI/MUI between July 1, 2014 and June 30, 2016 were identified using International Classification of Diseases 9 and 10 codes for SUI or MUI with the date of first diagnosis as the index date from which 2-year postindex healthcare resource use and direct cost data were derived from claims, examined, and compared 1:1 with patients without a SUI/MUI diagnosis, matched by age and Charlson's Comorbidity Index. RESULTS: A total of 68 636 women with SUI/MUI were matched 1:1 with controls. In the 2-year postindex date, a significantly higher proportion of SUI/MUI patients had ≥1 inpatient visit and ≥1 outpatient visit compared to the control group (inpatient: 18.89% vs. 12.10%, p < 0.0001; outpatient: 88.44% vs. 73.23%, p < 0.0001). Mean primary care visits were significantly higher in SUI/MUI patients compared to controls (7.33 vs. 5.53; p < 0.0001) as were specialist visits (1.2 vs. 0.08; p < 0.0001). Mean all-cause outpatient costs were higher in SUI/MUI patients compared to controls ($7032.10 vs. $3348.50; p < 0.0001), as were inpatient costs ($3990.70 vs. $2313.70; p < 0.0001). CONCLUSION: Women with SUI/MUI consume significantly higher medical resources and incur higher costs to payers, compared to women without SUI/MUI. While reasons for this are not fully understood, improved and standardized treatment for women with SUI/MUI may positively affect cost and outcomes.

Adherence to professional society guidelines among women with stress or mixed urinary incontinence.

AIMS: The objective of this analysis was to describe longitudinal adherence with recommended urinary incontinence (UI) evaluation and treatment guidelines over a 2-year period in patients newly diagnosed with stress (SUI) or mixed UI (MUI), and average 2-year cost associated with initial treatment. METHODS: A retrospective claims analysis using the IBM MarketScan database was conducted. Women diagnosed with SUI/MUI between July 1, 2014 and June 30, 2016 were identified using the International Classification of Diseases (ICD) 9 and 10 codes for SUI or MUI. Newly diagnosed SUI/MUI patients who did not have a UI-related diagnosis for at least 1 year before their index date were assessed. RESULTS: 103 813 patients with newly diagnosed SUI or MUI were identified. Of those, 96.15% (99 821/103 813) received an initial evaluation in accordance with professional guidelines (e.g., patient history, physical examination, urinalysis). Only 6.8% (5086/74 925) and 7.7% (2229/28 888) of patients with SUI and MUI, respectively, received a first-line behavioral treatment (e.g., pelvic floor muscle exercises, bladder training), according to guidelines. The 2-year average UI-related medical costs associated with guideline adherence for SUI were $5770.93 ± $9454.81 and for MUI, $4416.16 ± $7401.53. Nonadherence was observed in 59.2% (44 382/74 925) of SUI and 64.1% (18 530/28 888) of MUI patients. Two-year average UI-related medical costs for the nonadherent group were $8568.00 ± $11 275.52 for SUI and $6986.66 ± $10 765.55 for MUI, significantly more than the adherent group (p < 0.0001). CONCLUSION: The majority of SUI or MUI patients do not receive a documented behavioral intervention as their first-line treatment, which is a recommendation by professional society guidelines. This was found to affect the cost burden for payers; those that were nonadherent had significantly higher costs 2-year postindex.

Correction: Dynamic landscape of protein occupancy across the Escherichia coli chromosome.

[This corrects the article DOI: 10.1371/journal.pbio.3001306.].

Retrospective claims analysis of physical therapy utilization among women with stress or mixed urinary incontinence.

OBJECTIVE: To describe the characteristics of women with stress or mixed urinary incontinence (SUI/MUI) receiving physical therapy (PT) services, including referral patterns and PT utilization. METHODS: Female patients with claims associated with an SUI or MUI diagnosis (International Classification of Disease-Clinical Modification [ICD-9-CM]: 625.6, 788.33, or ICD-10-CM: N39.3, N39.46) between July 01, 2014 and June 30, 2016 were identified in International business machines (IBM)'s MarketScan Research Database. Inclusion criteria included the absence of pregnancy claims and ≥80% medical and pharmacy enrollment pre- and postindex. First SUI/MUI diagnosis claim determined index. Patients were followed for 2 years, and associated UI-associated PT encounters were identified. Descriptive statistics were calculated for patients with at least one PT visit during the postindex period. RESULTS: In a cohort of 103,813 women with incident SUI or MUI diagnosis, 2.6% (2792/103,813) had at least one PT visit in the 2 years following their diagnosis. Mean age at index PT encounter was 50.55 years. A total of 52.36% (1462/2792) women had one to four PT visits; 21.2% (592/2792) had >8 PT visits. In subanalysis of the PT cohort (1345/2792), women who received PT only had the lowest average 2-year postindex total medical cost (mean: $12,671; SD: $16,346), compared with PT plus medications (mean: $27,394; SD: $64,481), and PT plus surgery (mean: $33,656; SD: $26,245), respectively. Over 40% had their first PT visit ≥3 months after their index date. CONCLUSIONS: The percentage of women with a PT visit associated with an incident SUI or MUI diagnosis was low (2.6%), and 30% of this group completed three or more PT visits. This suggests poor adherence to clinical guidelines regarding supervised treatment of UI in women. IMPACT STATEMENT: Our study suggests underutilization of PT among insured women with SUI and MUI in the 2 years following diagnosis. Interventions to improve this gap in first-line care may represent an opportunity for an increased role for PTs in the care of women with UI.

US payer budget impact of a microarray assay with machine learning to evaluate kidney transplant rejection in for-cause biopsies.

AIM: This study evaluates the economic impact to US commercial payers of MMDx-Kidney used in conjunction with histologic evaluation of for-cause kidney transplant biopsies. MATERIALS AND METHODS: An Excel-based model was developed to assess the cost impact of histology plus MMDx-Kidney versus histology alone for the evaluation of potential rejection in kidney transplant patients who receive a for-cause biopsy. Different model time periods were assessed, ranging from 1 to 5 years post-biopsy. A targeted literature review was used to identify parameter estimates, validated by two external clinicians with expertise in managing kidney transplant rejection. A sensitivity analysis was conducted to evaluate the relative impact of key clinical and cost parameters. In particular, the model identified the magnitude of MMDx-Kidney's impact on graft failure from rejection that would be required for MMDx-Kidney to be cost-neutral. RESULTS: By more accurately characterizing rejection, MMDx-Kidney is estimated to increase antirejection treatment costs by $1,126 per test. Nevertheless, a break-even analysis shows that the costs of MMDx-Kidney and anti-rejection medication, as well as the costs associated with an increase in the number of patients with functioning transplants, may be offset by reductions in costs associated with graft failure (i.e. costs of hospitalizations, dialysis, and repeat transplants) over 5 years, assuming MMDx-Kidney reduces annual graft failure from rejection by at least 5%. For the base case, with a 25% relative reduction in annual rate of graft failures from rejection, MMDx-Kidney increases overall costs incurred in the first year of the model but starts generating savings by the second year of the model. CONCLUSIONS: Compared with histologic evaluation of for-cause kidney transplant biopsies alone, the use of MMDx-Kidney in conjunction with histologic evaluation improves the diagnoses of graft dysfunction and may have the potential to generate overall savings from reductions in rejection-related graft failure.

Dasiglucagon demonstrates reduced costs in the treatment of severe hypoglycemia in a budget impact model.

BACKGROUND: Approximately 7.3 million people with type 1 or type 2 diabetes (T1D/T2D) are treated with insulin, placing them at higher risk of severe hypoglycemia (SH). SH requires assistance of another individual and often necessitates the prompt administration of intravenous glucose, injectable glucagon, or both. Untreated, SH can progress to unconsciousness, seizures, coma, or death. Before 2018, all glucagon rescue treatments required reconstitution. The complexity of reconstitution is often a barrier to successful administration during a severe hypoglycemic event. Studies suggest successful administration of glucagon emergency kits range from 6%-56% of the time. Second-generation glucagon treatments and glucagon analogs do not require reconstitution and have caregiver administration success rates ranging from 94%-100%. Dasiglucagon is a glucagon analog administered via autoinjector or prefilled syringe and has been shown to result in rapid hypoglycemia recovery. Moreover, the autoinjector can be administered successfully 94% of the time by trained caregivers. Previous evaluation of costs in budget impact models (BIMs) demonstrated the potential for second-generation glucagon treatments to reduce the cost of SH events (SHEs). The current model expands on those findings with a treatment pathway and accompanying assumptions reflecting important aspects of real-world SHE treatment. OBJECTIVE: To evaluate the economic impact of dasiglucagon compared with available glucagon treatments for SHE management, considering direct cost of treatment and health care resource utilization. METHODS: A 1-year BIM with a hypothetical US commercial health plan of 1 million lives was developed with a target population of individuals with diabetes at risk of SHE. The treatment pathway model included initial and secondary treatment attempts, treatment administration success and failure, plasma glucose (PG) recovery within 15 minutes, emergency medical services, emergency department (ED) visits, and hospitalizations. A 1-way sensitivity analysis was conducted to assess the sensitivity of the model to changes in parameter values. RESULTS: In a 1 million-covered lives population, it was estimated that 12,006 SHEs would occur annually. The higher rate of initial treatment success and PG recovery within 15 minutes associated with dasiglucagon treatment resulted in lower total health care costs. Total SHE treatment costs with dasiglucagon were estimated at $13.4 million, compared with $16.7 million for injectable native glucagon, $20.7 million for nasal glucagon, $35.3 million for reconstituted glucagon, and $43.8 million for untreated individuals. Compared with untreated people, the number needed to treat (NNT) with dasiglucagon was 6 individuals to avoid 1 hospitalization. NNT for this same comparison was 59 for injectable native glucagon and 27 for nasal glucagon. CONCLUSIONS: Treatment of SH with dasiglucagon decreased total direct medical costs by reducing health care resource utilization (emergency calls, emergency transports, ED visits, and hospitalizations) and accompanying costs associated with the treatment of SH. DISCLOSURES: This research was funded by Zealand Pharma. Bromley, Hinahara, and Goss are employed by Boston Healthcare Associates, Inc., which received funding from Zealand Pharma for development of the health economic model and the manuscript. Kendall and Hammer are employed by Zealand Pharma. Weinzimer has received consulting fees from Zealand Pharma.

Distinct heterochromatin-like domains promote transcriptional memory and silence parasitic genetic elements in bacteria.

There is increasing evidence that prokaryotes maintain chromosome structure, which in turn impacts gene expression. We recently characterized densely occupied, multi-kilobase regions in the E. coli genome that are transcriptionally silent, similar to eukaryotic heterochromatin. These extended protein occupancy domains (EPODs) span genomic regions containing genes encoding metabolic pathways as well as parasitic elements such as prophages. Here, we investigate the contributions of nucleoid-associated proteins (NAPs) to the structuring of these domains, by examining the impacts of deleting NAPs on EPODs genome-wide in E. coli and B. subtilis. We identify key NAPs contributing to the silencing of specific EPODs, whose deletion opens a chromosomal region for RNA polymerase binding at genes contained within that region. We show that changes in E. coli EPODs facilitate an extra layer of transcriptional regulation, which prepares cells for exposure to exotic carbon sources. Furthermore, we distinguish novel xenogeneic silencing roles for the NAPs Fis and Hfq, with the presence of at least one being essential for cell viability in the presence of domesticated prophages. Our findings reveal previously unrecognized mechanisms through which genomic architecture primes bacteria for changing metabolic environments and silences harmful genomic elements.

Health-Related Quality of Life as Measured by the 36-Item Short Form Survey Among Adults With Acute Bacterial Skin and Skin Structure Infections who Received Either Omadacycline or Linezolid in a Phase 3 Double-Blind, Double-Dummy Clinical Trial.

This analysis of data from a Phase 3 study of adults with acute bacterial skin and skin structure infections showed that successful oral treatment with omadacycline (n = 368) or linezolid (n = 367) was associated with improvement in health-related quality of life.

Payer budget impact of an artificial intelligence in vitro diagnostic to modify diabetic kidney disease progression.

AIM: To evaluate the U.S. payer budget-impact of KidneyIntelX, an artificial intelligence-enabled in vitro diagnostic to predict kidney function decline in Type 2 Diabetic Kidney Disease (T2DKD) patients, stages 1-3b. MATERIALS AND METHODS: We developed an Excel-based model according to International Society of Pharmacoeconomics and Outcomes Research (ISPOR) good practices to assess U.S. payer budget impact associated with the use of the KidneyIntelX test to optimize therapy T2DKD patients compared to standard of care (SOC) (without KidneyIntelX). A hypothetical cohort of 100,000 stages 1-3b T2DKD patients was followed for 5 years. Peer-reviewed publications were used to identify model parameter estimates. KidneyIntelX costs incremental to SOC (without KidneyIntelX) included test cost, additional prescription medication use, specialist referrals and PCP office visits. Patients managed with KidneyIntelX experienced a 20% slowed progression rate compared to SOC (without KidneyIntelX) attributed to slowed DKD progression, delayed or prevented dialysis and transplants, and reduced dialysis crashes. Associated costs were compared to SOC (without KidneyIntelX). Sensitivity analyses were conducted by varying the definition of progression and the DKD progression rate associated with KidneyIntelX testing and related interventions. RESULTS: Projected undiscounted base case 5-year savings for 100,000 patients tested with KidneyIntelX were $1.052 billion, attributed mostly to slowed progression through DKD stages. The breakeven point for the health plan adopting KidneyIntelX is expected to occur prior to year 2 after adoption. Sensitivity analysis based on the assessment of the most conservative definition of progression and a 5% reduction in progression rate attributed to KidneyIntelX, resulted in a projected 5-year savings of $145 million associated with KidneyIntelX. LIMITATIONS AND CONCLUSIONS: Limitations included reliance on literature-based parameter estimates, including effect size of delayed progression supported by the literature. Incorporating KidneyIntelX in contemporary care of early-stage T2DKD patients is projected to result in substantial savings to payers.

Dynamic landscape of protein occupancy across the Escherichia coli chromosome.

Free-living bacteria adapt to environmental change by reprogramming gene expression through precise interactions of hundreds of DNA-binding proteins. A predictive understanding of bacterial physiology requires us to globally monitor all such protein-DNA interactions across a range of environmental and genetic perturbations. Here, we show that such global observations are possible using an optimized version of in vivo protein occupancy display technology (in vivo protein occupancy display-high resolution, IPOD-HR) and present a pilot application to Escherichia coli. We observe that the E. coli protein-DNA interactome organizes into 2 distinct prototypic features: (1) highly dynamic condition-dependent transcription factor (TF) occupancy; and (2) robust kilobase scale occupancy by nucleoid factors, forming silencing domains analogous to eukaryotic heterochromatin. We show that occupancy dynamics across a range of conditions can rapidly reveal the global transcriptional regulatory organization of a bacterium. Beyond discovery of previously hidden regulatory logic, we show that these observations can be utilized to computationally determine sequence specificity models for the majority of active TFs. Our study demonstrates that global observations of protein occupancy combined with statistical inference can rapidly and systematically reveal the transcriptional regulatory and structural features of a bacterial genome. This capacity is particularly crucial for non-model bacteria that are not amenable to routine genetic manipulation.

A qualitative study documenting unmet needs in the management of diabetic kidney disease (DKD) in the primary care setting.

BACKGROUND: A majority of diabetic kidney disease (DKD) patients receive medical care in the primary care setting, making it an important opportunity to improve patient management. There is limited evidence evaluating whether primary care physicians (PCPs) are equipped to effectively manage these patients in routine clinical practice. The present study was undertaken to identify gaps in primary care and unmet needs in the diagnosis and monitoring of DKD in type 2 diabetes (T2D) patients among PCPs. METHODS: This was a qualitative analysis based on 30-45-min interviews with PCPs treating T2D patients. PCPs were recruited via email and were board-certified, in practice for more than 3 years, spent most of their time in direct clinical care, and provided care for more than three T2D patients in a week. Descriptive data analysis was conducted to identify and examine themes that were generated by interviews. Two reviewers evaluated interview data to identify themes and developed consensus on the priority themes identified. RESULTS: A total of 16 PCPs satisfying the inclusion criteria were recruited for qualitative interviews. Although the PCPs recognized kidney disease as an important comorbidity in T2D patients, testing for kidney disease was not consistently top of mind, with 56% reportedly performing kidney function testing in their T2D patients. PCPs most frequently reported using estimated glomerular filtration rate (eGFR) alone to monitor and stage DKD; only 25% PCPs reported testing for albuminuria. Most PCPs incorrectly believed that a majority of DKD patients are diagnosed in early stages. Also, early stages of DKD emerged as ambiguous areas of decision-making, wherein treatments prescribed greatly varied among PCPs. Lastly, early and accurate risk stratification of DKD patients emerged as the most important unmet need; which, if it could be overcome, was consistently identified by PCPs as a key to monitoring, appropriate nephrologist referrals, and intervening to improve outcomes in patients with DKD. CONCLUSIONS: Our study highlights important unmet needs in T2D DKD testing, staging, and stratification in the PCP setting that limit effective patient care. Health systems and insurers in the U.S. should prioritize the review and approval of new strategies that can improve DKD staging and risk stratification.

Evaluation of the Economic Benefit of Earlier Systemic Lupus Erythematosus (SLE) Diagnosis Using a Multivariate Assay Panel (MAP).

OBJECTIVE: Diagnosis of systemic lupus erythematosus (SLE) made by standard diagnostic laboratory tests (SDLTs) has sensitivity and specificity of 83% and 76%, respectively. A multivariate assay panel (MAP) combining complement C4d activation products on erythrocytes and B cells with SDLTs yields a sensitivity and specificity of 80% and 86%, respectively, presumably enabling earlier SLE diagnosis at lower severity, with associated lower health care costs compared with SDLT diagnoses. We compared the payer budget impact of diagnosing SLE using MAP (incremental cost of $108) versus SDLTs. METHODS: We modeled a health plan of 1 million enrollees. SLE diagnosis among suspected patients was 9.2%. The MAP arm assumed 80%/20% of patients were tested with MAP/SDLTs, versus 100% tested with SDLTs in the SDLT arm. Prediagnosis direct costs were estimated from claims data, and postdiagnosis costs were obtained from the literature. Based on improved MAP performance, the assumed hazard ratio for diagnosis rate compared with SDLTs was 1.74 (71%, 87%, 90%, and 91% of patients who develop SLE are diagnosed in years 1 to 4 compared with 53%, 75%, 84%, and 88% of patients diagnosed with SDLTs). RESULTS: Total 4-year pre- and postdiagnosis direct costs for patients with suspected SLE tested with MAP were $59 183 666 compared with $61 174 818 tested by SDLTs, with lower costs in the MAP arm due primarily to prediagnosis savings related to reduced hospital admissions. CONCLUSION: Incorporating MAP into SLE diagnosis results in estimated 4-year direct cost savings of $1 991 152 ($0.04 per member per month). By facilitating earlier diagnosis of SLE, MAP may enhance patient outcomes.

Treatment Patterns and Medication Use in Patients with Postherpetic Neuralgia.

BACKGROUND: Postherpetic neuralgia (PHN) is a chronic, painful condition characterized by persistent pain following resolution of a herpes zoster (HZ) infection. Epidemiologic data demonstrate that the risks for HZ infections and the development of PHN increase with age. OBJECTIVE: To characterize prescribing patterns, health care utilization, and treatment costs for adults with PHN based on real-world data. METHODS: This study analyzed medical and pharmacy claims from 2010 to 2014 in the MarketScan Commercial and Medicare Supplemental databases. PHN patients were identified based on criteria from a published algorithm. PHN treatment patterns were analyzed by age and reported descriptively for patients aged < 65 or ≥ 65 years. Excess incremental health care costs were calculated for PHN patients by comparing expenditures for a cohort of PHN patients to expenditures of a propensity score-matched control group of patients with HZ alone. RESULTS: Approximately 0.4% of patients aged < 65 years were diagnosed with HZ versus 1.3% of patients aged ≥ 65 years; approximately 15.3% of HZ patients aged < 65 years and 26.4% of patients aged ≥ 65 years were diagnosed with PHN. Overall, opioids remained the most frequently prescribed initial treatment. Approximately 21.6% of PHN patients received an opioid as an initial treatment for PHN, 15.1% received gabapentin; 8.9% received a prescription nonsteroidal anti-inflammatory drug (NSAID); 8.3% received a lidocaine patch; 3.3% received pregabalin; 2.5% received a tricyclic antidepressants (TCAs); 0.8% received other topical lidocaine; and < 1% received capsaicin. Observed first-line use of the lidocaine patch and gabapentin was higher in patients aged ≥ 65 years relative to patients aged < 65 years. When separated by age group, only 24.6% of patients aged < 65 years and 38.5% of patients aged ≥ 65 years were prescribed a recommended first-line treatment for initial PHN therapy (gabapentin, lidocaine patch, pregabalin, and TCAs). Comparisons of treatment costs of PHN patients to matched HZ patients without PHN indicated that PHN patients initiated on opioids had the highest mean additional health care expenditure compared with PHN patients initiated on other medications. On average, PHN patients initiated on opioids had $7,601 additional health care expenditure compared with HZ patients with no PHN; additional expenditures were $6,428 for pregabalin, $4,213 for lidocaine patches, $3,478 for gabapentin, $3,304 for NSAIDs, and $2,797 for TCAs, respectively. CONCLUSIONS: Management of PHN is associated with substantial utilization of opioid-based therapies across all ages. Medications supported by evidence either as first-line therapies or as part of a multimodal regimen for the management of PHN are underused relative to opioid-based PHN therapies. Improving adherence to evidence-based PHN treatment regimens offers the potential to reduce opioid prescribing first line and reduce overall treatment costs. Given the emphasis to reduce opioid prescribing to minimize the risk of dependence, abuse, and diversion, multimodal analgesic treatments that can avoid or reduce opioid use should be considered. DISCLOSURES: Research funding was provided by SCILEX Pharmaceuticals. The sponsor reviewed and approved the research plan and provided support for manuscript preparation through Patel's role as a coauthor of this manuscript. The sponsor's product (lidocaine patch) was not used in this study. Patel is a paid employee of SCILEX Pharmaceuticals. Goss is an employee and minority owner of Boston Healthcare Associates, which received a research grant from SCILEX Pharmaceuticals to conduct this study. Gudin reports advisory board fees from AcelRx Pharmaceuticals and BioDelivery Sciences International and consulting fees from Averitas, Daiichi, Hisumitsu, Nektar, Purdue, Quest Diagnostics, SCILEX Pharmaceuticals, and US WorldMeds, unrelated to this study. Fudin reports advisory board fees from AcelRx Pharmaceuticals, Human Half-Cell, Quest Diagnostics, GlaxoSmithKline, SCILEX Pharmaceuticals, BioDelivery Sciences, Daiichi Sankyo, and Salix Pharmaceuticals; speaker fees from Daiichi Sankyo, Salix Pharmaceuticals, Abbott Laboratories, Acutis Diagnostics, and AstraZeneca; and consulting fees from Firstox Laboratories, unrelated to this study. The other authors have nothing to disclose. Parts of this research were presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting; April 22, 2016; San Francisco, CA, and at the 35th Annual Scientific Meeting of the American Pain Society; May 11-14, 2016; Austin, TX.

Stool DNA Analysis is Cost-Effective for Colorectal Cancer Surveillance in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Patients with chronic ulcerative colitis are at increased risk for colorectal neoplasia (CRN). Surveillance by white-light endoscopy (WLE) or chromoendoscopy may reduce risk of CRN, but these strategies are underused. Analysis of DNA from stool samples (sDNA) can detect CRN with high levels of sensitivity, but it is not clear if this approach is cost-effective. We simulated these strategies for CRN detection to determine which approach is most cost-effective. METHODS: We adapted a previously published Markov model to simulate the clinical course of chronic ulcerative colitis, the incidence of cancer or dysplasia, and costs and benefits of care with 4 surveillance strategies: (1) analysis of sDNA and diagnostic chromoendoscopy for patients with positive results, (2) analysis of sDNA with diagnostic WLE for patients with positive results, (3) chromoendoscopy with targeted collection of biopsies, or (4) WLE with random collection of biopsies. Costs were based on 2014 Medicare reimbursement. The primary outcome was the incremental cost-effectiveness ratio (incremental cost/incremental difference in quality-adjusted life-years) compared with no surveillance and a willingness-to-pay threshold of $50,000. RESULTS: All strategies fell below the willingness-to-pay threshold at 2-year intervals. Incremental cost-effectiveness ratios were $16,362 per quality-adjusted life-year for sDNA analysis with diagnostic chromoendoscopy; $18,643 per quality-adjusted life-year for sDNA analysis with diagnostic WLE; $23,830 per quality-adjusted life-year for chromoendoscopy alone; and $27,907 per quality-adjusted life-year for WLE alone. In sensitivity analyses, sDNA analysis with diagnostic chromoendoscopy was more cost-effective than chromoendoscopy alone, up to a cost of $1135 per sDNA test. sDNA analysis remained cost-effective at all rates of compliance; when combined with diagnostic chromoendoscopy, this approach was preferred over chromoendoscopy alone, when the specificity of the sDNA test for CRN was >65%. CONCLUSIONS: Based on a Markov model, surveillance for CRN is cost-effective for patients with chronic ulcerative colitis. Analysis of sDNA with chromoendoscopies for patients with positive results was more cost-effective than chromoendoscopy or WLE alone.

Demonstrating Value for Biosimilars: A Conceptual Framework.

BACKGROUND: The value proposition for biosimilars can be characterized as a concept that moves beyond the argument of cost reduction relative to the innovator biologic drug and into a framework that incorporates the diverse needs of key healthcare stakeholders during the transition from clinical development to commercialization in the marketplace. OBJECTIVES: To identify factors that facilitate and inhibit the development, commercialization, and adoption of biosimilars, and to recommend modifications in program design that are likely to support the demonstration of the value of biosimilars for payers, providers, and patients. METHODS: The primary data sources for this article include surveys conducted by Boston Healthcare Associates with payers and clinicians in the United States and the European Union 5 markets and blinded international protocol feasibility assessments completed by Worldwide Clinical Trials. Survey methodology used either convenience or purposeful sampling as appropriate, with participants extracted from diverse audiences, representative of those who generate or evaluate clinical data shaping the economic exchange and preferential status influencing physician adoption and patient access to biosimilars. Patient characteristics and psychosocial issues influencing patients' perception of small-molecule generics were extracted from the available literature to inform exploratory hypotheses, given the relative absence of such information for biosimilars. DISCUSSION: This article reviews the current evidence and summarizes results of surveys conducted with payers, providers, and drug investigation sites in the United States. Based on a review of published literature, as well as these survey results, conflicting and convergent demands exist for gathering data related to biosimilars. The motivations and data needs for these new agents are diverse, requiring adjudication of regulatory, economic, and clinical incentives beginning at program inception and extending through commercialization of the final biosimilar agent. CONCLUSIONS: The development and commercialization of biosimilars represent an international activity that can encounter unanticipated challenges, as well as opportunities to achieve clinical and commercial success. Evolving regulatory guidance mapped in relation to payer, physician, and patient sentiments may inform the biosimilar development program designs, implementation, and positioning of the new drug.

Assessment of motivating factors associated with the initiation and completion of treatment for chronic hepatitis C virus (HCV) infection.

BACKGROUND: Infection with hepatitis C virus (HCV) is associated with high morbidity and increased mortality but many patients avoid initiation of treatment or report challenges with treatment completion. The study objective was to identify motivators and barriers for treatment initiation and completion in a community sample of HCV-infected patients in the United States. METHODS: Survey methods were employed to identify factors reported by patients as important in their decision to start or complete HCV treatment. Study participants included 120 HCV-infected individuals: 30 had previously completed treatment with pegylated interferon/ribavirin (PR), 30 had discontinued PR, 30 were treated with PR at the time of the survey, and 30 were treatment‒naïve. Telephone interviews occurred between May and August of 2011 and employed a standardized guide. Participants assigned factors a rating from 1 (not at all important) to 5 (extremely important). Trained researchers coded and analyzed interview transcripts. RESULTS: Of 33 factors, expected health problems from not treating HCV infection was reported as most encouraging for treatment initiation and completion, while treatment side effects was most discouraging. Sixty-nine percent of participants reported that the ability to obtain information during treatment on the likelihood of treatment success (i.e., results of viral load testing) would motivate them to initiate therapy. Median preferred timing for learning about test results was 5 weeks (range: 1-23 weeks). CONCLUSION: Understanding challenges and expectations from patients is important in identifying opportunities for education to optimize patient adherence to their HCV treatment regimen.