Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

Use of a Blood Biomarker Test Improves Economic Utility in the Evaluation of Older Patients Presenting with Cognitive Impairment.

More than 16 million Americans living with cognitive impairment warrant a diagnostic evaluation to determine the cause of this disorder. The recent availability of disease-modifying therapies for Alzheimer's disease (AD) is expected to significantly drive demand for such diagnostic testing. Accurate, accessible, and affordable methods are needed. Blood biomarkers (BBMs) offer advantages over usual care amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in these regards. This study used a budget impact model to assess the economic utility of the PrecivityAD® blood test, a clinically validated BBM test for the evaluation of brain amyloid, a pathological hallmark of AD. The model compared 2 scenarios: (1) baseline testing involving usual care practice, and (2) early use of a BBM test before usual care CSF and PET biomarker use. At a modest 40% adoption rate, the BBM test scenario had comparable sensitivity and specificity to the usual care scenario and showed net savings in the diagnostic work-up of $3.57 million or $0.30 per member per month in a 1 million member population, translating to over $1B when extrapolated to the US population as a whole and representing a 11.4% cost reduction. Savings were driven by reductions in the frequency and need for CSF and PET testing. Additionally, BBM testing was associated with a cost savings of $643 per AD case identified. Use of the PrecivityAD blood test in the clinical care pathway may prevent unnecessary testing, provide cost savings, and reduce the burden on both patients and health plans.

Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aß42/40 ratio to identify presence of brain amyloid.

BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

A polygenic risk score added to a QRISK®2 cardiovascular disease risk calculator demonstrated robust clinical acceptance and clinical utility in the primary care setting.

AIMS: The aim of the study was to assess the real-world feasibility, acceptability, and impact of an integrated risk tool for cardiovascular disease (CVD IRT, combining the standard QRISK®2 risk algorithm with a polygenic risk score), implemented within routine primary practice in the UK National Health Service. METHODS AND RESULTS: The Healthcare Evaluation of Absolute Risk Testing Study (NCT05294419) evaluated participants undergoing primary care health checks. Both QRISK2 and CVD IRT scores were returned to the healthcare providers (HCPs), who then communicated the results to participants. The primary outcome of the study was feasibility of CVD IRT implementation. Secondary outcomes included changes in CVD risk (QRISK2 vs. CVD IRT) and impact of the CVD IRT on clinical decision-making. A total of 832 eligible participants (median age 55 years, 62% females, 97.5% White ethnicity) were enrolled across 12 UK primary care practices. Cardiovascular disease IRT scores were obtained on 100% of the blood samples. Healthcare providers stated that the CVD IRT could be incorporated into routine primary care in a straightforward manner in 90.7% of reports. Participants stated they were 'likely' or 'very likely' to recommend the use of this test to their family or friends in 86.9% of reports. Participants stated that the test was personally useful (98.8%) and that the results were easy to understand (94.6%). When CVD IRT exceeded QRISK2, HCPs planned changes in management for 108/388 (27.8%) of participants and 47% (62/132) of participants with absolute risk score changes of >2%. CONCLUSION: Amongst HCPs and participants who agreed to the trial of genetic data for refinement of clinical risk prediction in primary care, we observed that CVD IRT implementation was feasible and well accepted. The CVD IRT results were associated with planned changes in prevention strategies.

When a standard cardiovascular risk tool, as currently used in National Health Service Health Checks, was expanded to include genetic risk information, it was well accepted by both participants and healthcare providers and generated impactful changes in planned clinical decision-making.Most participants found the test useful and easy to understand, and healthcare providers found it straightforward to use in most cases.When risk was increased by the addition of genetic information, this influenced planned management decisions.

A blood biomarker test for brain amyloid impacts the clinical evaluation of cognitive impairment.

OBJECTIVE: The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. METHODS: The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. RESULTS: A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). INTERPRETATION: These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.

The Clinical Utility of a Precision Medicine Blood Test Incorporating Age, Sex, and Gene Expression for Evaluating Women with Stable Symptoms Suggestive of Obstructive Coronary Artery Disease: Analysis from the PRESET Registry.

Background: Evaluating women with symptoms suggestive of coronary artery disease (CAD) remains challenging. A blood-based precision medicine test yielding an age/sex/gene expression score (ASGES) has shown clinical validity in the diagnosis of obstructive CAD. We assessed the effect of the ASGES on the management of women with suspected obstructive CAD in a community-based registry. Materials and Methods: The prospective PRESET (A Registry to Evaluate Patterns of Care Associated with the Use of Corus® CAD in Real World Clinical Care Settings) Registry (NCT01677156) enrolled 566 patients presenting with symptoms suggestive of stable obstructive CAD from 21 United States primary care practices from 2012 to 2014. Demographics, clinical characteristics, and referrals to cardiology or further functional and/or anatomical cardiac studies after ASGES testing were collected for this subgroup analysis of women from the PRESET Registry. Patients were followed for 1-year post-ASGES testing. Results: This study cohort included 288 women with a median age 57 years. The median body mass index was 29.2, with hyperlipidemia and hypertension present in 48% and 43% of patients, respectively. Median ASGES was 8.5 (range 1-40), with 218 (76%) patients having low (≤15) ASGES. Clinicians referred 9% (20/218) low ASGES versus 44% (31/70) elevated ASGES women for further cardiac evaluation (odds ratio 0.14, p < 0.0001, adjusted for patient demographics and clinical covariates). Across the score range, higher ASGES were associated with a higher likelihood of posttest cardiac referral. At 1-year follow-up, low ASGES women experienced fewer major adverse cardiac events than elevated ASGES women (1.3% vs. 4.2% respectively, p = 0.16). Conclusions: Incorporation of ASGES into the diagnostic workup demonstrated clinical utility by helping clinicians identify women less likely to benefit from further cardiac evaluation.

Economic Outcomes of a Precision Medicine Blood Test To Assess Obstructive Coronary Artery Disease: Results from the PRESET Registry.

PURPOSE: The evaluation of obstructive coronary artery disease (CAD) is inefficient and costly. Previous studies of an age/sex/gene expression score (ASGES) in this diagnostic workup have shown a 96% negative predictive value, as well as an 85% decreased likelihood of cardiac referral among low-score outpatients at 45 days. The objective was to explore the one-year cost implications of ASGES use among symptomatic outpatients. DESIGN: A prospective PRESET Registry (NCT01677156) enrolled stable, nonacute adult patients presenting with symptoms suggestive of obstructive CAD at 21 U.S. primary care practices. METHODOLOGY: Demographics, clinical factors, and ASGES (defined as low <=15 or elevated >15), as well as management plans post-ASGES, were collected. The economic endpoint analysis was based on the cost of cardiovascular-related tests, procedures, office visits, emergency room visits, and hospitalizations during one year after testing. RESULTS: The analysis included 566 patients, 51% of whom were women and the median age was 56. Forty-five percent had a low ASGES. The mean cost of cardiovascular care for patients in the year following ASGES was $1,647 for patients with a low ASGES versus $2,709 for those with an elevated score (39% reduction, P=.03 by Wilcoxon rank test). This relationship remained after multivariate analysis that adjusted for patient demographics and clinical covariates (P<.001). CONCLUSION: The ASGES helped identify patients with low current likelihood of obstructive CAD. These patients had lower costs of cardiovascular care during one year of follow-up. Early reductions in cardiac referrals at 45 days among these patients persisted at one year.

Utility of a Precision Medicine Test in Elderly Adults with Symptoms Suggestive of Coronary Artery Disease.

BACKGROUND: Diagnosing obstructive coronary artery disease (CAD) is challenging in elderly adults, and current diagnostic approaches for CAD expose these individuals to risks from contrast dye and invasive procedures. DESIGN: A Registry to Evaluate Patterns of Care Associated with the Use of Corus CAD in Real World Clinical Care Settings (PRESET; NCT01677156), pragmatic clinical trial. SETTING: Community, 21 primary care practices. PARTICIPANTS: Of 566 stable, nonacute outpatients presenting with symptoms suggestive of obstructive CAD, the 176 who were aged 65 and older (median age 70, 61% female) were the current study participants. INTERVENTION: Blood-based precision medicine test, incorporating age, sex, and gene expression score (ASGES) to improve clinical decision-making and quality of care. MEASUREMENTS: Information on demographic characteristics, clinical factors, ASGES results (range 1-40; low (≤15), high (>15)), referral patterns to cardiology and advanced cardiac testing, and major adverse cardiac events (MACEs) was collected in a subgroup analysis of elderly adults in the PRESET Registry. Follow-up was for 1 year after ASGES testing. RESULTS: Median ASGES was 25, and 40 (23%) participants had a low score. Clinicians referred 12.5% of participants with a low ASGES and 49.3% with a high ASGES to cardiology or advanced cardiac testing (odds ratio for referral = 0.12, P < .001, adjusted for participants demographics and clinical covariates). Higher scores were associated with greater likelihood of posttest cardiac referral. At 1-year follow-up, the incidence of a MACE or revascularization was 10% (13/136) in the high ASGES group and 0% (0/40) in the low ASGES group (P = .04). CONCLUSION: The ASGES test showed potential clinical utility in the evaluation of elderly outpatients with symptoms suggestive of obstructive CAD. Test use may reduce unnecessary referrals and the risk of procedure-related complications in individuals with low ASGES, who are unlikely to benefit from further testing, while also identifying individuals who may benefit from further cardiac evaluation and management.

An age- and sex-specific gene expression score is associated with revascularization and coronary artery disease: Insights from the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial.

BACKGROUND: Identifying predictors of coronary artery disease (CAD)-related procedures and events remains a priority. METHODS: We measured an age- and sex-specific gene expression score (ASGES) previously validated to detect obstructive CAD (oCAD) in symptomatic nondiabetic patients in the PROMISE trial. The outcomes were oCAD (≥70% stenosis in ≥1 vessel or ≥50% left main stenosis on CT angiography [CTA]) and a composite endpoint of death, myocardial infarction, revascularization, or unstable angina. RESULTS: The ASGES was determined in 2370 nondiabetic participants (47.5% male, median age 59.5 years, median follow-up 25 months), including 1137 with CTA data. An ASGES >15 was associated with oCAD (odds ratio 2.5 [95% CI 1.6-3.8], P<.001) and the composite endpoint (hazard ratio [HR] 2.6 [95% CI 1.8-3.9], P<.001) in unadjusted analyses. After adjustment for Framingham risk, an ASGES >15 remained associated with the composite endpoint (P=.02); the only component that was associated was revascularization (adjusted HR 2.69 [95% CI 1.52-4.79], P<.001). Compared to noninvasive testing, the ASGES improved prediction for the composite (increase in c-statistic=0.036; continuous net reclassification index=43.2%). Patients with an ASGES ≤15 had a composite endpoint rate no different from those with negative noninvasive test results (3.2% vs. 2.6%, P=.29). CONCLUSIONS: A blood-based genomic test for detecting oCAD significantly predicts near-term revascularization procedures, but not non-revascularization events. Larger studies will be needed to clarify the risk with non-revascularization events.

Clinical Utility of a Precision Medicine Test Evaluating Outpatients with Suspected Obstructive Coronary Artery Disease.

BACKGROUND: Identifying patients with obstructive coronary artery disease can be challenging for primary care physicians. Advances in precision medicine may help augment clinical tools and redefine the paradigm for evaluating coronary artery disease in the outpatient setting. A blood-based age/sex/gene expression score (ASGES) incorporating key features of precision medicine has shown clinical validity with a 96% negative predictive value and 89% sensitivity in estimating a symptomatic patient's current likelihood of obstructive coronary artery disease. To better characterize the clinical utility of the ASGES and measure its impact on clinician decision-making, a community-based registry was established. METHODS: The prospective PRESET Registry (NCT01677156) enrolled stable, nonacute adult patients presenting with typical or atypical symptoms suggestive of obstructive coronary artery disease from 21 US primary care practices from August 2012 to August 2014. Demographics, clinical characteristics, and ASGES results (predefined as low [ASGES ≤15] or elevated [ASGES >15]) were collected, as were referrals to Cardiology or further functional/anatomic cardiac testing after ASGES testing. Patients were followed for 1 year post ASGES testing. RESULTS: Among the 566-patient cohort (median age 56 years), clinicians referred 26/252 (10%) of patients with low scores vs 137/314 (44%) of patients with elevated scores to Cardiology or advanced cardiac testing for further evaluation (unadjusted odds ratio 0.15, P <.0001; adjusted odds ratio after accounting for clinical covariates = 0.18, P <.0001). Data on 84 patients referred for advanced cardiac testing showed abnormal findings in 0 of 13 (0%) low ASGES and 10 of 71 (14%) elevated ASGES patients. Major adverse cardiovascular events and revascularization were noted in 3/252 (1.2%) patients with low ASGES and 14/314 (4.5%) patients with elevated ASGES score (P <.03). CONCLUSIONS: In this community-based cardiovascular registry, the ASGES demonstrated clinical utility in the evaluation of patients with suspected obstructive coronary artery disease. Low-score patients were less likely to undergo cardiac referral, were unlikely to have positive findings on further cardiac work-up, and had a low rate of adverse cardiovascular events in 1-year follow-up. Our work provides evidence supporting the value of using precision medicine in the delivery of cardiovascular care.

Use of a blood test incorporating age, sex, and gene expression influences medical decision-making in the evaluation of women presenting with symptoms suggestive of obstructive coronary artery disease: summary results from two ambulatory care studies in primary care.

OBJECTIVE: Clinicians need better approaches to evaluating women at midlife and beyond who present to primary care with chest pain and related symptoms. A previously validated blood-based test, which includes age, sex, and gene expression levels, showed a 96% negative predictive value for determining an individual's current likelihood of having obstructive coronary artery disease (CAD) in a combined population of men and women. We hypothesized that age/sex/gene expression score (ASGES) would be incorporated into medical decision-making and would influence the rate of further cardiac evaluation. METHODS: An aggregate analysis of female cohorts from the Investigation of a Molecular Personalized Coronary Gene Expression Test on Primary Care Practice Pattern (IMPACT-PCP; NCT01594411) and REGISTRY I (NCT01557855) studies was conducted. Data on 320 women presenting with stable symptoms suggestive of obstructive CAD and undergoing ASGES testing (from 16 primary care providers in geographically diverse sites) were pooled. The primary outcome of this analysis was the association between ASGES and referrals for further cardiac evaluation. RESULTS: The mean participant age was 57.8 years, and the mean ASGES (predefined as low [ASGES ≤15] or elevated [ASGES >15]) was 10.3. The referral rate for further cardiac evaluation was 4.0% (10 of 248) for women with low ASGES versus 83.3% (60 of 72) for women with elevated ASGES, with an overall follow-up major adverse cardiac event/revascularization rate of 1.2%. After adjustment for clinical covariates, women with low ASGES were significantly less likely to be referred for further cardiac evaluation (odds ratio, 0.013; P < 0.0001). CONCLUSIONS: ASGES can be incorporated into medical decision-making to help primary care providers rule out obstructive CAD among symptomatic women who are unlikely to benefit from further cardiac testing.

The diagnosis of CAD in women: addressing the unmet need - a report from the national expert roundtable meeting.

A multistakeholder panel comprising experts in the fields of clinical cardiology, medical technology innovation, women's health research and policy analysis, personalized medicine, payers (including self-insured employers), patient advocacy, and health economics was convened at the Heart House in Washington, DC. The following points emerged as key concepts: (1) Diagnostic challenges in the evaluation of women with symptoms suggestive of obstructive coronary artery disease (CAD) result from: (a) presentation with atypical symptoms and lower pretest probability of disease compared to men, (b) fatty tissue and breast tissue attenuation on cardiac imaging leading to false positive findings, and (c) the presence of microvascular CAD. (2) Diagnostic challenges lead to both over-testing of low-risk women and under-testing of high-risk women. (3) Efforts should be directed toward increasing clinician, clinical professional society, and consumer awareness and understanding of sex-specific differences between men and women in the pathophysiology of CAD. (4) Multiple health care stakeholders should be made aware of new advances in genomic approaches to address the challenges of diagnosing obstructive CAD; specifically, the Corus CAD gene expression test, which was shown to have high sensitivity and negative predictive value in a recent clinical trial. As such, it has promise as a tool to help clinicians to rule out obstructive CAD as a cause of a patient's symptoms. (Population Health Management 2015;18:86-92).

Enhanced assessment of chest pain and related symptoms in the primary care setting through the use of a novel personalized medicine genomic test: results from a prospective registry study.

Novel approaches for assessing patients with chest pain and related symptoms may improve outpatient care. The REGISTRY I study measured the impact of a personalized gene expression score (GES) on subsequent cardiac referral decisions by primary care providers. Of the 342 stable, nonacute patients evaluated, the mean age was 55 years, 53% were female, and mean (SD) GES was 16 (±10) (range = 1-40). Low GES (≤15), indicating a low current likelihood of obstructive coronary artery disease (CAD), was observed in 49% of patients. After clinical covariate adjustment, each 10-point GES decrease was associated with a 14-fold decreased odds of cardiac referral (P < .0001). Low GES patients had 94% reduced odds of referral relative to elevated GES patients (P < .0001), with follow-up supporting a favorable safety profile. This genomic-based test demonstrated clinical utility by guiding decision making during assessment of symptomatic patients with suspected obstructive CAD.

Utility of a genomic-based, personalized medicine test in patients presenting with symptoms suggesting coronary artery disease.

PURPOSE: Better methods are needed to assess patients presenting with symptoms suggestive of obstructive coronary artery disease (CAD). We hypothesized that the use of a gene expression score (GES) would lead to a change in the diagnostic evaluation. METHODS: The Primary Care Providers Use of a Gene Expression Test in Coronary Artery Disease Diagnosis (IMPACT-PCP) trial (clinical trial identifier NCT01594411, clinicaltrials.gov) was a prospective study of stable, nonacute, nondiabetic patients presenting with chest pain and related symptoms at 4 primary care practices. All patients underwent GES testing, with clinicians documenting their planned diagnostic strategy both before and after GES. The GES was derived from a peripheral blood draw measuring expression of 23 genes and has been shown to have a 96% negative predictive value for excluding the diagnosis of obstructive CAD. RESULTS: Of the 251 study patients, 140 were women (56%); the participants had a mean age of 56 years (standard deviation, 13.0) and a mean body mass index of 30 mg/kg(2) (standard deviation, 6.7). The mean GES was 16 (range, 1-38), and 127 patients (51%) had a low GES ([ltqeu]15). A change in the diagnostic testing pattern before and after GES testing was noted in 145 of 251 patients (58% observed vs. 10% predefined expected change; P < .001). CONCLUSIONS: Incorporation of the GES into the diagnostic workup showed clinical utility above and beyond conventional clinical factors by optimizing the patient's diagnostic evaluation.

Economic utility of a blood-based genomic test for the assessment of patients with symptoms suggestive of obstructive coronary artery disease.

Approximately 3 million patients with symptoms suggestive of obstructive coronary artery disease (CAD) present to primary care offices in the United States annually, resulting in approximately $6.7 billion in cardiac workup costs. Despite wide application of existing diagnostic technologies, yield of obstructive CAD at invasive coronary angiography (ICA) is low. This study used a decision analysis model to assess the economic utility of a novel gene expression score (GES) for the diagnosis of obstructive CAD. Within a representative commercial health plan's adult membership, current practice for obstructive CAD diagnosis (usual care) was compared to a strategy that incorporates the GES test (GES-directed care). The model projected the number of diagnostic tests and procedures performed, the number of patients receiving medical therapy, type I and type II errors for each strategy of obstructive CAD diagnosis, and the associated costs over a 1-year time horizon. Results demonstrate that GES-directed care to exclude the diagnosis of obstructive CAD prior to myocardial perfusion imaging may yield savings to health plans relative to usual care by reducing utilization of noninvasive and invasive cardiac imaging procedures and increasing diagnostic yield at ICA. At a 50% capture rate of eligible patients in GES-directed care, it is projected that a commercial health plan will realize savings of $0.77 per member per month; savings increase proportionally to the GES capture rate. These findings illustrate the potential value of this new blood-based, molecular diagnostic test for health plans and patients in an age of greater emphasis on personalized medicine.

Clinical implications of referral bias in the diagnostic performance of exercise testing for coronary artery disease.

BACKGROUND: Exercise testing with echocardiography or myocardial perfusion imaging is widely used to risk-stratify patients with suspected coronary artery disease. However, reports of diagnostic performance rarely adjust for referral bias, and this practice may adversely influence patient care. Therefore, we evaluated the potential impact of referral bias on diagnostic effectiveness and clinical decision-making. METHODS AND RESULTS: Searching PubMed and EMBASE (1990-2012), 2 investigators independently evaluated eligibility and abstracted data on study characteristics and referral patterns. Diagnostic performance reported in 4 previously published meta-analyses of exercise echocardiography and myocardial perfusion imaging was adjusted using pooled referral rates and Bayesian methods. Twenty-one studies reported referral patterns in 49 006 patients (mean age 60.7 years, 39.6% women, and 0.8% prior history of myocardial infarction). Catheterization referral rates after normal and abnormal exercise tests were 4.0% (95% CI, 2.9% to 5.0%) and 42.5% (36.2% to 48.9%), respectively, with odds ratio for referral after an abnormal test of 14.6 (10.7 to 19.9). After adjustment for referral, exercise echocardiography sensitivity fell from 84% (80% to 89%) to 34% (27% to 41%), and specificity rose from 77% (69% to 86%) to 99% (99% to 100%). Similarly, exercise myocardial perfusion imaging sensitivity fell from 85% (81% to 88%) to 38% (31% to 44%), and specificity rose from 69% (61% to 78%) to 99% (99% to 100%). Summary receiver operating curve analysis demonstrated only modest changes in overall discriminatory power but adjusting for referral increased positive-predictive value and reduced negative-predictive value. CONCLUSIONS: Exercise echocardiography and myocardial perfusion imaging are considerably less sensitive and more specific for coronary artery disease after adjustment for referral. Given these findings, future work should assess the comparative ability of these and other tests to rule-in versus rule-out coronary artery disease.

The clinical utility of gene expression testing on the diagnostic evaluation of patients presenting to the cardiologist with symptoms of suspected obstructive coronary artery disease: results from the IMPACT (Investigation of a Molecular Personalized Coronary Gene Expression Test on Cardiology Practice Pattern) trial.

Accurate, noninvasive evaluation for obstructive coronary artery disease (CAD) remains challenging and inefficient. In this study, 171 patients presenting with stable chest pain and related symptoms without a history of CAD were referred to 6 cardiologists for evaluation. In the prospective cohort of 88 patients, the cardiologist's diagnostic strategy was evaluated before and after gene expression score (GES) testing. The GES is a validated, quantitative blood-based diagnostic test measuring peripheral blood cell expression levels of 23 genes to determine the likelihood of obstructive CAD (at least 1 vessel with ≥ 50% angiographic coronary artery stenosis). The objective of the study was to measure the effect of the GES on diagnostic testing using a pre/post study design. There were 83 prospective patients evaluable for study analysis, which included 57 (69%) women, mean age 53 ± 11 years, and mean GES 12.5 ± 9. Presenting symptoms were classified as typical angina, atypical angina, and noncardiac chest pain in 33%, 60%, and 7% of patients (n = 27, 50, and 6), respectively. After GES, changes in diagnostic testing occurred in 58% of patients (n = 48, P < 0.001). Of note, 91% (29/32) of patients with decreased testing had low GES (≤ 15), whereas 100% (16/16) of patients with increased testing had elevated GES (P < 0.001). A historical cohort of 83 patients, matched to the prospective cohort by clinical factors, had higher diagnostic test use compared with the post-GES prospective cohort (P < 0.001). In summary, the GES showed clinical utility in the evaluation of patients with suspected obstructive CAD presenting to the cardiologist's office.

Agitation and depression in frail nursing home elderly patients with dementia: treatment characteristics and service use.

OBJECTIVE: The authors describe characteristics, treatment, and acute service use associated with agitation and depression in dementia. METHODS: Authors used retrospective chart review of symptoms, physician-level prescribing, and acute service use over 3 months for 2,487 physically frail older residents, including 1,836 with dementia, (mean age: 79.8 years) in 109 long-term care facilities, describing differences between uncomplicated dementia and three mutually exclusive subgroups of complicated dementia, including dementia with agitation-only, dementia with depression-only, and dementia with mixed agitation and depression. RESULTS: Compared with the other subgroups, frail elderly patients with dementia complicated by mixed agitation and depression have the highest rate of hospitalization, the greatest number of medical diagnoses, and the greatest medical severity, and they receive the greatest number of psychiatric medications. Depression in dementia (either alone or mixed with agitation) was associated with greater prevalence of pain. CONCLUSIONS: Dementia complicated by mixed agitation and depression accounts for over one-third of complicated dementia and is associated with multiple psychiatric and medical needs, intensive pharmacological treatment, and use of high-cost services. Research should target this complex, high-risk group to develop appropriate diagnostic criteria and effective treatment interventions.