Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions.

PURPOSE: This study aimed to estimate the cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children. METHODS: We modeled costs, diagnoses, and quality-adjusted life years (QALYs) for diagnostic strategies for critically ill infants (aged <1 year) and children (aged <18 years) with suspected genetic conditions: (1) standard of care (SOC) testing, (2) ES, (3) GS, (4) SOC followed by ES, (5) SOC followed by GS, (6) ES followed by GS, and (7) SOC followed by ES followed by GS. We calculated the 10-year incremental cost per additional diagnosis, and lifetime incremental cost per QALY gained, from a health care perspective. RESULTS: First-line GS costs $15,048 per diagnosis vs SOC for infants and $27,349 per diagnosis for children. If GS is unavailable, ES represents the next most efficient option compared with SOC ($15,543 per diagnosis for infants and $28,822 per diagnosis for children). Other strategies provided the same or fewer diagnoses at a higher incremental cost per diagnosis. Lifetime results depend on the patient's assumed long-term prognosis after diagnosis. For infants, GS ranged from cost-saving (vs all alternatives) to $18,877 per QALY (vs SOC). For children, GS (vs SOC) ranged from $119,705 to $490,047 per QALY. CONCLUSION: First-line GS may be the most cost-effective strategy for diagnosing infants with suspected genetic conditions. For all children, GS may be cost-effective under certain assumptions. ES is nearly as efficient as GS and hence is a viable option when GS is unavailable.

Cost-effectiveness of genome sequencing for diagnosing patients with undiagnosed rare genetic diseases.

PURPOSE: To estimate the cost-effectiveness of genome sequencing (GS) for diagnosing critically ill infants and noncritically ill pediatric patients (children) with suspected rare genetic diseases from a United States health sector perspective. METHODS: A decision-analytic model was developed to simulate the diagnostic trajectory of patients. Parameter estimates were derived from a targeted literature review and meta-analysis. The model simulated clinical and economic outcomes associated with 3 diagnostic pathways: (1) standard diagnostic care, (2) GS, and (3) standard diagnostic care followed by GS. RESULTS: For children, costs of GS ($7284) were similar to that of standard care ($7355) and lower than that of standard care followed by GS pathways ($12,030). In critically ill infants, when cost estimates were based on the length of stay in the neonatal intensive care unit, the lowest cost pathway was GS ($209,472). When only diagnostic test costs were included, the cost per diagnosis was $17,940 for standard, $17,019 for GS, and $20,255 for standard care followed by GS. CONCLUSION: The results of this economic model suggest that GS may be cost neutral or possibly cost saving as a first line diagnostic tool for children and critically ill infants.

The diagnostic trajectory of infants and children with clinical features of genetic disease.

We characterized US pediatric patients with clinical indicators of genetic diseases, focusing on the burden of disease, utilization of genetic testing, and cost of care. Curated lists of diagnosis, procedure, and billing codes were used to identify patients with clinical indicators of genetic disease in healthcare claims from Optum's de-identified Clinformatics® Database (13,076,038 unique patients). Distinct cohorts were defined to represent permissive and conservative estimates of the number of patients. Clinical phenotypes suggestive of genetic diseases were observed in up to 9.4% of pediatric patients and up to 44.7% of critically-ill infants. Compared with controls, patients with indicators of genetic diseases had higher utilization of services (e.g., mean NICU length of stay of 31.6d in a cohort defined by multiple congenital anomalies or neurological presentations compared with 10.1d for patients in the control population (P < 0.001)) and higher overall costs. Very few patients received any genetic testing (4.2-8.4% depending on cohort criteria). These results highlight the substantial proportion of the population with clinical features associated with genetic disorders and underutilization of genetic testing in these populations.

Multi-Institutional, Prospective Clinical Utility Study Evaluating the Impact of the 92-Gene Assay (CancerTYPE ID) on Final Diagnosis and Treatment Planning in Patients With Metastatic Cancer With an Unknown or Unclear Diagnosis.

PURPOSE: Metastatic cancers of unknown primary or with unclear diagnoses pose diagnostic and management challenges, often leading to poor outcomes. Studies of the 92-gene assay have demonstrated improved diagnostic accuracy compared with standard pathology techniques and improved survival in patients treated on the basis of assay results. The current study assessed the clinical impact of the 92-gene assay on diagnostic and treatment decisions for patients with unknown or uncertain diagnoses. METHODS: Patients in this prospective, multi-institutional, decision-impact study included those for whom the 92-gene assay was ordered as part of routine care. Participating physicians completed electronic case report forms that contained standardized, specialty-specific questionnaires. Data collection included patient and tumor characteristics and clinical history. The key study objective of clinical impact was calculated on the basis of changes in final diagnosis and treatment after testing. RESULTS: Data collection included 444 patients, 107 physicians (73 oncologists and 34 pathologists), and 28 sites. Molecular diagnoses from 22 different tumor types and subtypes across all cases were provided in 95.5% of patients with a reportable result (n = 397). Physicians reported that the 92-gene assay was used broadly for diagnostic dilemmas that ranged from single suspected tumor type (29%) to a differential diagnosis of two or more suspected tumor types (30%) or cancers of unknown primary (41%). Integration of 92-gene assay results led to a change in the recommended treatment in 47% of patients. CONCLUSION: Findings from this clinical utility study demonstrate that the 92-gene assay led to a change in treatment decisions in every other patient case. These data additionally define the role of this assay in clinical practice and strongly support the consideration of molecular tumor typing in the diagnosis and treatment planning of patients with metastatic cancer with unknown or uncertain diagnosis.

A Novel Breast Cancer Index for Prediction of Distant Recurrence in HR+ Early-Stage Breast Cancer with One to Three Positive Nodes.

Purpose: The study objective was to characterize the prognostic performance of a novel Breast Cancer Index model (BCIN+), an integration of BCI gene expression, tumor size, and grade, specifically developed for assessment of distant recurrence (DR) risk in HR+ breast cancer patients with one to three positive lymph nodes (pN1).Experimental Design: Analysis was conducted in a well-annotated retrospective series of pN1 patients (N = 402) treated with adjuvant endocrine therapy with or without chemotherapy using a prespecified model. The primary endpoint was time-to-DR. Results were determined blinded to clinical outcome. Kaplan-Meier estimates of overall (0-15 years) and late (≥5 years) DR, HRs, and 95% confidence interval (CIs) were estimated. Likelihood ratio statistics assessed relative contributions of prognostic information.Results: BCIN+ classified 81 patients (20%) as low risk with a 15-year DR rate of 1.3% (95% CI, 0.0%-3.7%) versus 321 patients as high risk with a DR rate of 29.0% (95% CI, 23.2%-34.4%). In patients DR-free for ≥5 years (n = 349), the late DR rate was 1.3% (95% CI, 0.0%-3.7%) and 16.1% (95% CI, 10.6%-21.3%) in low- and high-risk groups, respectively. BCI gene expression alone was significantly prognostic (ΔLR-χ2 = 20.12; P < 0.0001). Addition of tumor size (ΔLR-χ2 = 13.29, P = 0.0003) and grade (ΔLR-χ2 = 12.72; P = 0.0004) significantly improved prognostic performance. BCI added significant prognostic information to tumor size (ΔLR-χ2 = 17.55; P < 0.0001); addition to tumor grade was incremental (ΔLR-χ2 = 2.38; P = 0.1) with considerable overlap between prognostic values (ΔLR-χ2 = 17.74).Conclusions: The integrated BCIN+ identified 20% of pN1 patients with limited risk of recurrence over 15 years, in whom extended endocrine treatment may be spared. Ongoing studies will characterize combined clinical-genomic risk assessment in node-positive patients. Clin Cancer Res; 23(23); 7217-24. ©2017 AACR.

Cross-Stratification and Differential Risk by Breast Cancer Index and Recurrence Score in Women with Hormone Receptor-Positive Lymph Node-Negative Early-Stage Breast Cancer.

PURPOSE: Previous results from the TransATAC study demonstrated that both the Breast Cancer Index (BCI) and the OncotypeDX Recurrence Score (RS) added significant prognostic information to clinicopathologic factors over a 10-year period. Here, we examined cross-stratification between BCI and RS to directly compare their prognostic accuracy at the individual patient level. EXPERIMENTAL DESIGN: A total of 665 patients with hormone receptor-positive (HR+) and lymph node-negative disease were included in this retrospective analysis. BCI and RS risk groups were determined using predefined clinical cut-off points. Kaplan-Meier estimates of 10-year risk of distant recurrence (DR) and log-rank tests were used to examine cross-stratification between BCI and RS. RESULTS: As previously reported, both RS and BCI were significantly prognostic in years 0 to 10. BCI provided significant additional prognostic information to the Clinical Treatment Score (CTS) plus RS (ΔLR-χ2 = 11.09; P < 0.001), whereas no additional prognostic information was provided by RS to CTS plus BCI (ΔLR-χ2 = 2.22; P = 0.1). Restratification by BCI of the low and intermediate RS risk groups led to subgroups with significantly different DR rates (P < 0.001 and P = 0.003, respectively). In contrast, restratified subgroups created by RS of BCI risk groups did not differ significantly. CONCLUSIONS: In this retrospective analysis, BCI demonstrated increased prognostic accuracy versus RS. Notably, BCI identified subsets of RS low and RS intermediate risk patients with significant and clinically relevant rates of DR. These results indicate that additional subsets of women with HR+, lymph node-negative breast cancer identified by BCI may be suitable candidates for adjuvant chemotherapy or extended endocrine therapy. Clin Cancer Res; 22(20); 5043-8. ©2016 AACRSee related commentary by Brufsky and Davidson, p. 4963.

Molecular classification of cancer with the 92-gene assay in cytology and limited tissue samples.

BACKGROUND: Detailed molecular evaluation of cytology and limited tissue samples is increasingly becoming the standard for cancer care. Reproducible and accurate diagnostic approaches with reduced demands on cellularity are an ongoing unmet need. This study evaluated the performance of a 92-gene assay for molecular diagnosis of tumor type/subtype in cytology and limited tissue samples. METHODS: Clinical validation of accuracy for the 92-gene assay in limited tissue samples such as cytology cell blocks, core biopsies and small excisions was conducted in a blinded multi-institutional study (N = 109, 48% metastatic, 53% grade II and III). Analytical success rate and diagnostic utility were evaluated in a consecutive series of 644 cytology cases submitted for clinical testing. RESULTS: The 92-gene assay demonstrated 91% sensitivity (95% CI [0.84, 0.95]) for tumor classification, with high accuracy maintained irrespective of specimen type (100%, 92%, and 86% in FNA/cytology cell blocks, core biopsies, and small excisions, respectively; p = 0.26). The assay performed equally well for metastatic versus primary tumors (90% vs 93%, p = 0.73), and across histologic grades (100%, 90%, 89%, in grades I, II, and III, respectively; p = 0.75). In the clinical case series, a molecular diagnosis was reported in 87% of the 644 samples, identifying 23 different tumor types and allowing for additional mutational analysis in selected cases. CONCLUSIONS: These findings demonstrate high accuracy and analytical success rate of the 92-gene assay, supporting its utility in the molecular diagnosis of cancer for specimens with limited tissue.

Cost effectiveness of a 92-gene assay for the diagnosis of metastatic cancer.

OBJECTIVES: To estimate the clinical and economic trade-offs involved in using a molecular assay (92-gene assay, CancerTYPE ID) to aid in identifying the primary site of difficult-to-diagnose metastatic cancers and to explore whether the 92-gene assay can be used to standardize the diagnostic process and costs for clinicians, patients, and payers. METHODS: Four decision-analytic models were developed to project the lifetime clinical and economic impact of incorporating the 92-gene assay compared with standard care alone. For each model, total and incremental costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and the proportion of patients treated correctly versus incorrectly were projected from the payer perspective. Model inputs were based on published literature, analyses of SEER (Surveillance Epidemiology and End RESULTS) data, publicly available data, and interviews with clinical experts. RESULTS: In all four models, the 92-gene assay increased the proportion of patients treated correctly, decreased the proportion of patients treated with empiric therapy, and increased quality-adjusted survival. In the primary model, the ICER was $50,273/QALY; thus, the 92-gene assay is therefore cost effective when considering a societal willingness-to-pay threshold of $100,000/QALY. These findings were robust across sensitivity analyses. CONCLUSIONS: Use of the 92-gene assay for diagnosing metastatic tumors of uncertain origin is associated with reduced misdiagnoses, increased survival, and improved quality of life. Incorporating the assay into current practice is a cost-effective approach to standardizing diagnostic methods while improving patient care. Limitations of this analysis are the lack of data availability and resulting modeling simplifications, although sensitivity analyses showed these to not be key drivers of results.

Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence.

PURPOSE: Residual risk of relapse remains a substantial concern for patients with hormone receptor-positive breast cancer, with approximately half of all disease recurrences occurring after five years of adjuvant antiestrogen therapy. EXPERIMENTAL DESIGN: The objective of this study was to examine the prognostic performance of an optimized model of Breast Cancer Index (BCI), an algorithmic gene expression-based signature, for prediction of early (0-5 years) and late (>5 years) risk of distant recurrence in patients with estrogen receptor-positive (ER(+)), lymph node-negative (LN(-)) tumors. The BCI model was validated by retrospective analyses of tumor samples from tamoxifen-treated patients from a randomized prospective trial (Stockholm TAM, n = 317) and a multi-institutional cohort (n = 358). RESULTS: Within the Stockholm TAM cohort, BCI risk groups stratified the majority (∼65%) of patients as low risk with less than 3% distant recurrence rate for 0 to 5 years and 5 to 10 years. In the multi-institutional cohort, which had larger tumors, 55% of patients were classified as BCI low risk with less than 5% distant recurrence rate for 0 to 5 years and 5 to 10 years. For both cohorts, continuous BCI was the most significant prognostic factor beyond standard clinicopathologic factors for 0 to 5 years and more than five years. CONCLUSIONS: The prognostic sustainability of BCI to assess early- and late-distant recurrence risk at diagnosis has clinical use for decisions of chemotherapy at diagnosis and for decisions for extended adjuvant endocrine therapy beyond five years.

Development and validation of a 32-gene prognostic index for prostate cancer progression.

The accurate determination of the risk of cancer recurrence is an important unmet need in the management of prostate cancer. Patients and physicians must weigh the benefits of currently available therapies against the potential morbidity of these treatments. Herein we describe the development of a gene expression-based continuous risk index and a validation of this test in an independent, blinded cohort of post-radical prostatectomy (RP) patients. A gene expression signature, prognostic for prostate-specific antigen (PSA) recurrence, was identified through a bioinformatic analysis of the expression of 1,536 genes in malignant prostate tissue from a training cohort of consecutive patients treated with RP. The assay was transferred to a real-time RT-PCR platform, and a continuous risk index model was constructed based on the expression of 32 genes. This 32-gene risk index model was validated in an independent, blinded cohort of 270 RP patients. In multivariate analyses, the risk index was prognostic for risk of PSA recurrence and had added value over standard prognostic markers such as Gleason score, pathologic tumor stage, surgical margin status, and presurgery PSA (hazard ratio, 4.05; 95% confidence interval, 1.50-10.94; P = 0.0057). Furthermore, RP patients could be stratified based on the risk of PSA recurrence and the development of metastatic disease. The 32-gene signature identified here is a robust prognostic marker for disease recurrence. This assay may aid in postoperative treatment selection and has the potential to impact decision making at the biopsy stage.

Blinded comparator study of immunohistochemical analysis versus a 92-gene cancer classifier in the diagnosis of the primary site in metastatic tumors.

Accurate tumor classification is fundamental to inform predictive biomarker testing and optimize therapy. Gene expression-based tests are proposed as diagnostic aids in cases with uncertain diagnoses. This study directly compared the diagnostic accuracy of IHC analysis versus molecular classification using a 92-gene RT-PCR assay for determination of the primary tumor site. This prospectively defined blinded study of diagnostically challenging cases included 131 high-grade, primarily metastatic tumors. Cases were reviewed and reference diagnoses established through clinical correlation. Blinded FFPE sections were evaluated by either IHC/morphology analysis or the 92-gene assay. The final analysis included 122 cases. The 92-gene assay demonstrated overall accuracy of 79% (95% CI, 71% to 85%) for tumor classification versus 69% (95% CI, 60% to 76%) for IHC/morphology analysis (P = 0.019). Mean IHC use was 7.9 stains per case (median, 8; range, 2 to 15). IHC/morphology analysis accuracy was 79%, 80%, and 46% when 1 to 6 (n = 42), 7 to 9 (n = 41), and >9 (n = 39) IHC stains were used, respectively, versus 81%, 85%, and 69%, respectively, with the 92-gene assay. Results from this blinded series of high-grade metastatic cases demonstrate superior accuracy with the 92-gene assay versus standard-of-care IHC analysis and strongly support the diagnostic utility of molecular classification in difficult-to-diagnose metastatic cancer.

Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease.

Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer's disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer's disease.

Role of islet-, gut-, and adipocyte-derived hormones in the central control of food intake and body weight: implications for an integrated neurohormonal approach to obesity pharmacotherapy.

Contrary to its historical epithet as a lifestyle disorder, obesity is now widely recognized as having a neurobiological basis. This progress is due to our knowledge not only about energy homoeostatic pathways within the central nervous system (CNS), but also about the role of peripheral peptide hormones acting upon the CNS. These hormones include long-term adiposity signals, such as leptin, that inform the CNS primarily of changes in the body's overall fat and energy reserves, and short-term signals such as amylin, peptide YY (PYY) and ghrelin, that primarily reflect changes in the immediate nutritive state (energy intake). The limited weight loss effects achieved with current monotherapy approaches to obesity have been attributed, at least in part, to the redundancies and potent counter-regulatory responses within the neurohormonal feedback loop governing energy balance. Recently, we reported that combinations of amylin, leptin and PYY(3-36) resulted in additive and/or synergistic interactions and caused marked weight loss in the diet-induced obese rat model, which to date has reasonably predicted the clinical effects of several hormones in obese humans. If confirmed in ongoing translational clinical research studies, these findings may provide a physiological rationale for a novel, integrated neurohormonal approach to pharmacotherapy for obesity.

Pramlintide treatment reduces 24-h caloric intake and meal sizes and improves control of eating in obese subjects: a 6-wk translational research study.

Evidence from rodent studies indicates that the beta-cell-derived neurohormone amylin exerts multiple effects on eating behavior, including reductions in meal size, intake of highly palatable foods, and stress-induced sucrose consumption. To assess the effect of amylin agonism on human eating behavior we conducted a randomized, blinded, placebo-controlled, multicenter study investigating the effects of the amylin analog pramlintide on body weight, 24-h caloric intake, portion sizes, "fast food" intake, and perceived control of eating in 88 obese subjects. After a 2-day placebo lead-in, subjects self-administered pramlintide (180 microg) or placebo by subcutaneous injection 15 min before meals for 6 wk without concomitant lifestyle modifications. Compared with placebo, pramlintide treatment elicited significant mean reductions from baseline in body weight on day 44 (-2.1 +/- 0.3 vs. +0.1 +/- 0.4%, P < 0.001), 24-h caloric intake (-990 +/- 94 vs. -243 +/- 126 kcal on day 3, P < 0.0001; -680 +/- 86 vs. -191 +/- 161 kcal on day 43, P < 0.01), portion sizes, and caloric intake at a "fast food challenge" (-385 +/- 61 vs. -109 +/- 88 kcal on day 44, P < 0.05). Pramlintide treatment also improved perceived control of eating, as demonstrated by a 45% placebo-corrected reduction in binge eating scores (P < 0.01). The results of this translational research study confirm in humans various preclinical effects of amylin agonism, demonstrating that pramlintide-mediated weight loss in obese subjects is accompanied by sustained reductions in 24-h food intake, portion sizes, fast food intake, and binge eating tendencies.

Pramlintide acetate in the treatment of Type 2 and Type 1 diabetes mellitus.

Maintenance of glucose homeostasis involves the interplay of multiple glucoregulatory factors, including the pancreatic ß-cell hormones insulin and amylin. Amylin, a neuroendocrine hormone, is secreted in response to nutrient intake and suppresses postprandial glucagon secretion, helps regulate gastric emptying, and reduces food intake. Patients with diabetes are deficient in both insulin and amylin - contributing to postprandial hyperglycemia. Pramlintide, an analogue of amylin, is the active ingredient in the SYMLIN® (pramlintide acetate) injection. SYMLIN is indicated as an adjunctive treatment for insulin-using patients with diabetes and works through mechanisms similar to those of amylin. Clinical trials have demonstrated that pramlintide therapy improves postprandial glucose control, lowers A1C, and is accompanied by a reduction in body weight. Mild-to-moderate nausea and an increased risk of insulin-induced severe hypoglycemia have been the most common side effects. These side effects can be mitigated by gradual pramlintide dose escalation during treatment initiation and proactive mealtime insulin dose reduction upon initiation of pramlintide therapy.

Deficits in synaptic transmission and learning in amyloid precursor protein (APP) transgenic mice require C-terminal cleavage of APP.

Synaptic dysfunction has been shown to be one of the earliest correlates of disease progression in animal models of Alzheimer's disease. Amyloid-beta protein (Abeta) is thought to play an important role in disease-related synaptic dysfunction, but the mechanism by which Abeta leads to synaptic dysfunction is not understood. Here we describe evidence that cleavage of APP in the C terminus may be necessary for the deficits present in APP transgenic mice. In APP transgenic mice with a mutated cleavage site at amino acid 664, normal synaptic transmission, synaptic plasticity, and learning were maintained despite the presence of elevated levels of APP, Abeta42, and even plaque accumulation. These results indicate that cleavage of APP may play a critical role in the development of synaptic and behavioral dysfunction in APP transgenic mice.