Diagnosis and Severity Assessment of COPD Using a Novel Fast-Response Capnometer and Interpretable Machine Learning.

INTRODUCTION: Spirometry is the gold standard for COPD diagnosis and severity determination, but is technique-dependent, nonspecific, and requires administration by a trained healthcare professional. There is a need for a fast, reliable, and precise alternative diagnostic test. This study's aim was to use interpretable machine learning to diagnose COPD and assess severity using 75-second carbon dioxide (CO2) breath records captured with TidalSense's N-TidalTM capnometer. METHOD: For COPD diagnosis, machine learning algorithms were trained and evaluated on 294 COPD (including GOLD stages 1-4) and 705 non-COPD participants. A logistic regression model was also trained to distinguish GOLD 1 from GOLD 4 COPD with the output probability used as an index of severity. RESULTS: The best diagnostic model achieved an AUROC of 0.890, sensitivity of 0.771, specificity of 0.850 and positive predictive value (PPV) of 0.834. Evaluating performance on all test capnograms that were confidently ruled in or out yielded PPV of 0.930 and NPV of 0.890. The severity determination model yielded an AUROC of 0.980, sensitivity of 0.958, specificity of 0.961 and PPV of 0.958 in distinguishing GOLD 1 from GOLD 4. Output probabilities from the severity determination model produced a correlation of 0.71 with percentage predicted FEV1. CONCLUSION: The N-TidalTM device could be used alongside interpretable machine learning as an accurate, point-of-care diagnostic test for COPD, particularly in primary care as a rapid rule-in or rule-out test. N-TidalTM also could be effective in monitoring disease progression, providing a possible alternative to spirometry for disease monitoring.

Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization.

Over 100 million research participants around the world have had research array-based genotyping (GT) or genome sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to confirm and return pathogenic and likely pathogenic variants (PLPVs) in 59 genes. Variant verification prior to participant recontact revealed that GT falsely identified PLPVs in 44.9% of samples, and GT failed to identify 72.0% of PLPVs detected in a subset of samples that were also sequenced. GT and GS detected verified PLPVs in 1% and 2.5% of the cohort, respectively. Of 256 participants who were alerted that they carried actionable PLPVs, 37.5% actively or passively declined further disclosure. 76.3% of those carrying PLPVs were unaware that they were carrying the variant, and over half of those met published professional criteria for genetic testing but had never been tested. This gRoR protocol cost approximately $129,000 USD per year in laboratory testing and research staff support, representing $14 per participant whose DNA was analyzed or $3,224 per participant in whom a PLPV was confirmed and disclosed. These data provide logistical details around gRoR that could help other investigators planning to return genomic results.

Sequencing and imputation in GWAS: Cost-effective strategies to increase power and genomic coverage across diverse populations.

A key aim for current genome-wide association studies (GWAS) is to interrogate the full spectrum of genetic variation underlying human traits, including rare variants, across populations. Deep whole-genome sequencing is the gold standard to fully capture genetic variation, but remains prohibitively expensive for large sample sizes. Array genotyping interrogates a sparser set of variants, which can be used as a scaffold for genotype imputation to capture a wider set of variants. However, imputation quality depends crucially on reference panel size and genetic distance from the target population. Here, we consider sequencing a subset of GWAS participants and imputing the rest using a reference panel that includes both sequenced GWAS participants and an external reference panel. We investigate how imputation quality and GWAS power are affected by the number of participants sequenced for admixed populations (African and Latino Americans) and European population isolates (Sardinians and Finns), and identify powerful, cost-effective GWAS designs given current sequencing and array costs. For populations that are well-represented in existing reference panels, we find that array genotyping alone is cost-effective and well-powered to detect common- and rare-variant associations. For poorly represented populations, sequencing a subset of participants is often most cost-effective, and can substantially increase imputation quality and GWAS power.

Health Care Infrastructure for Financially Sustainable Clinical Genomics.

Next-generation sequencing has evolved technically and economically into the method of choice for interrogating the genome in cancer and inherited disorders. The introduction of procedural code sets for whole-exome and genome sequencing is a milestone toward financially sustainable clinical implementation; however, achieving reimbursement is currently a major challenge. As part of a prospective quality-improvement initiative to implement the new code sets, we adopted Agile, a development methodology originally devised in software development. We implemented eight functionally distinct modules (request review, cost estimation, preauthorization, accessioning, prebilling, testing, reporting, and reimbursement consultation) and obtained feedback via an anonymous survey. We managed 50 clinical requests (January to June 2015). The fraction of pursued-to-requested cases (n = 15/50; utilization management fraction, 0.3) aimed for a high rate of preauthorizations. In 13 of 15 patients the insurance plan required preauthorization, which we obtained in 70% and ultimately achieved reimbursement in 50%. Interoperability enabled assessment of 12 different combinations of modules that underline the importance of an adaptive workflow and policy tailoring to achieve higher yields of reimbursement. The survey confirmed a positive attitude toward self-organizing teams. We acknowledge the individuals and their interactions and termed the infrastructure: human pipeline. Nontechnical barriers currently are limiting the scope and availability of clinical genomic sequencing. The presented human pipeline is one approach toward long-term financial sustainability of clinical genomics.

Pharmacogenomic test that predicts response to inhaled corticosteroids in adults with asthma likely to be cost-saving.

AIM: To identify the clinical and economic circumstances under which a pharmacogenomic test that predicts response to inhaled corticosteroids might be a cost-effective option for individuals with asthma. MATERIALS & METHODS: We synthesized published data on clinical and economic outcomes to project 10-year costs, quality-adjusted life-years and cost-effectiveness of pharmacogenomic testing for inhaled corticosteroid response. We assumed the pharmacogenomic test cost was $500 with a sensitivity and specificity of 84 and 98%, respectively. These were varied in sensitivity analyses. RESULTS: Both strategies, pharmacogenomic testing for inhaled corticosteroid response and no testing conferred 7.1 quality-adjusted life-years. Compared with no testing, pharmacogenomic testing costs less. CONCLUSION: Pharmacogenomic testing for asthma is cost-saving and noninferior in improving health. Original submitted 19 November 2014; Revision submitted 23 February 2015.

Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort.

Patients with severe or difficult-to-treat asthma account for substantial asthma morbidity, mortality, and healthcare burden despite comprising only a small proportion of the total asthma population. TENOR, a multicenter, observational, prospective cohort study was initiated in 2001. It enrolled 4,756 adults, adolescents and children with severe or difficult-to-treat asthma who were followed semi-annually and annually for three years, enabling insight to be gained into this understudied population. A broad range of demographic, clinical, and patient self-reported assessments were completed during the follow-up period. Here, we present key findings from the TENOR registry in relation to asthma control and exacerbations, including the identification of specific subgroups found to be at particularly high-risk. Identification of the factors and subgroups associated with poor asthma control and increased risk of exacerbations can help physicians design individual asthma management, and improve asthma-related health outcomes for these patients.

Racial disparities in asthma-related health outcomes in severe or difficult-to-treat asthma.

BACKGROUND: The underlying reasons for racial disparities in asthma morbidity are not well understood. Multivariate epidemiologic studies evaluating the presence and extent of racial differences in a large cohort of adults with severe or difficult-to-treat asthma are lacking. OBJECTIVE: To analyze an extensive array of clinical and patient-reported outcomes, using multivariate analysis with a sequential approach, to explain racial differences in asthma-related outcomes in one of the largest cohorts of difficult-to-treat asthmatic patients. METHODS: Black and white patients (> or = 18-years-old at baseline) were included (n = 2,128). Differences between the 2 racial groups were assessed using several outcome measures at month 12. Assessments were adjusted for confounding variables using a sequence of statistical models. RESULTS: Most patients were white (88.6%). Blacks were slightly younger, less educated, and more likely to live in urban areas than whites. Blacks were more likely to have severe asthma and to be treated with 3 or more long-term controllers. Poorer quality of life, more asthma control problems, and higher risk of emergency department visits were observed in blacks compared with whites; differences were not explained by adjustment for broad sets of confounding variables. Differences in asthma-related health outcomes remained statistically significant after adjusting for asthma severity. CONCLUSIONS: Asthma is a serious health problem in blacks and is not explained by differences in demographics, severity, or other health conditions.

Insurance status and asthma-related health care utilization in patients with severe asthma.

BACKGROUND: Medicaid insurance has been associated with worse asthma outcomes, but the degree to which demographic factors contribute to this relationship has not been well explored. OBJECTIVE: To evaluate whether insurance status is independently associated with health care utilization (HCU) and asthma control when demographic differences are taken into account. METHODS: We used baseline data from adults with severe asthma in the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. HCU was defined as hospitalization or emergency department visit for asthma in the past 3 months. Asthma control was evaluated using the Asthma Therapy Assessment Questionnaire. Multiple logistic regression was used to compare HCU and asthma control in patients with Medicaid vs those with private health insurance. RESULTS: Of 1315 patients analyzed, 130 (9.9%) had Medicaid insurance and 1,185 (90.1%) had private insurance. Medicaid insurance was associated with younger age, female sex, race other than white, obesity, active smoking, lower education level, and unemployment. In unadjusted analyses, Medicaid patients had significantly higher HCU (odds ratio [OR], 3.08; 95% confidence interval [CI], 2.11-4.50) and poorer asthma control (OR, 2.56; 95% CI, 1.84-3.57) compared with patients with private insurance. After adjusting for demographic differences, insurance status was no longer associated with HCU (OR, 1.43; 95% CI, 0.92-2.23), and the strength of its association with asthma control was reduced (OR, 1.67; 95% CI, 1.17-2.40). CONCLUSIONS: Medicaid insurance is not associated with increased HCU in patients with severe asthma once demographic factors have been taken into account but remains modestly associated with poorer asthma control.

Modeling the potential impact of a prescription drug copayment increase on the adult asthmatic medicaid population.

OBJECTIVES: The Commonwealth of Massachusetts increased the copayment for prescription drugs by $1.50 for Medicaid (MassHealth) beneficiaries in 2003. We sought to determine the likely health outcomes and cost shifts attributable to this copayment increase using the example of inhaled corticosteroids (ICS) use among adult asthmatic Medicaid beneficiaries. METHOD: We compared the predicted costs and health outcomes projected over a 1-year time horizon with and without the increase in copayment from the perspective of MassHealth, providers, pharmacies, and MassHealth beneficiaries by employing decision analysis simulation model. RESULTS: In a target population of 17,500 adult asthmatics, increased copayments from 50 cent to $2.00 would result in an additional 646 acute events per year, caused by increased drug nonadherence. Annual combined net savings for the state and federal governments would be $2.10 million. Projected MassHealth savings are attributable to both decreased drug utilization and lower pharmacy reimbursement rates; these more than offset the additional costs of more frequent acute exacerbations. Pharmacies would lose $1.98 million in net revenues, MassHealth beneficiaries would pay an additional $0.28 million, and providers would receive additional $0.16 million. CONCLUSION: Over its first year of implementation, increase in the prescription drug copayment is expected to produce more frequent acute exacerbations among asthmatic MassHealth beneficiaries who use ICS and to shift the financial burden from government to other stakeholders.

Cost-effectiveness of omalizumab in adults with severe asthma: results from the Asthma Policy Model.

BACKGROUND: Omalizumab (trade name Xolair) is approved by the US Food and Drug Administration for treatment of moderate-to-severe allergic asthma. Given the high acquisition cost of omalizumab, its role and cost-effectiveness in disease management require definition. OBJECTIVE: We sought to identify the clinical and economic circumstances under which omalizumab might or might not be a cost-effective option by using a mathematic model. METHODS: We merged published data on clinical and economic outcomes (including acute event incidence, frequency/severity of hospitalizations, and health-related quality of life) to project 10-year costs, quality-adjusted life years (QALYs), and cost-effectiveness of treatment with omalizumab in addition to inhaled corticosteroids. Sensitivity analyses were conducted by using input data ranges from a variety of sources (published clinical trials and observational databases). RESULTS: For patients with baseline acute event rates, omalizumab conferred an additional 1.7 quality-adjusted months at an incremental cost of $131,000 over a 10-year planning horizon, implying a cost-effectiveness ratio of $821,000 per QALY gained. For patients with 5 times the baseline acute event rate, the cost-effectiveness ratio was $491,000 per QALY gained. The projected cost-effectiveness ratio could fall within a range of other programs that are widely considered to be cost-effective if the cost of omalizumab decreases to less than $200. CONCLUSION: Omalizumab is not cost-effective for most patients with severe asthma. The projected cost-effectiveness ratios could fall within a favorable range if the cost of omalizumab decreases significantly. CLINICAL IMPLICATIONS: Based on the high cost of omalizumab, it is especially important that clinicians explore alternative medications for asthma before initiating omalizumab.

Cost-effectiveness of inhaled steroids in asthma: impact of effect on bone mineral density.

BACKGROUND: The effects of inhaled corticosteroid (ICS) preparations on bone health have been debated. Multiple analyses have been published examining the question, with mixed results. OBJECTIVES: We examined how assumptions about the effect of ICS on bone mineral density (BMD) influence the cost-effectiveness of ICS in asthma. METHODS: We developed a mathematical simulation model to estimate clinical outcomes and costs for a cohort with mild/moderate asthma. The analysis conformed to reference case recommendations of the US Panel on Cost-Effectiveness in Health and Medicine. Sensitivity analysis evaluated the stability of our results to uncertainty in treatment duration, age at treatment, and ICS dose. RESULTS: Assuming a dose of 200 microg twice per day of ICS, a literature-based average effect of ICS on BMD and a 10-year time horizon, we observed a minimal increase in the costs attributed to hip fracture and incremental cost effectiveness ratio of $26,000 per quality-adjusted life-year and $14.00 per symptom-free day gained. Over an extended the time horizon (lifetime), the incremental cost effectiveness ratio increased to $42,000/quality-adjusted life-year. Only under a scenario of high-dose ICS, a lifetime horizon, and a large effect of ICS on BMD did the potential impact of ICS on BMD dramatically affect the economic attractiveness of therapy. CONCLUSION: To minimize any potential impact, use of the lowest effective dose of ICS and measures to target and intervene in high-risk individuals are warranted. However, ICS therapy in mild/moderate asthma compares favorably with commonly accepted interventions over a wide range of assumptions regarding this treatment and its effects on BMD.

Validity of the HEDIS criteria to identify children with persistent asthma and sustained high utilization.

BACKGROUND: The most widely used performance measure for asthma, the Health Plan Employer Data and Information Set (HEDIS), has been criticized because the delay between classification (year 1) and assessment of medication dispensing (year 2) may produce a "misalignment" and weaken the validity of the measure. OBJECTIVE: To examine whether a previously observed association between the HEDIS performance measure and asthma-related emergency department visits is robust when the period between the classification and outcome assessment is evaluated during a 2-year period as defined. METHODS: Children (N = 2766) aged 3 to 15 years enrolled in 1 of 3 managed care organizations with at least 1 asthma diagnosis listed for a hospitalization, an emergency department visit, or an ambulatory encounter and at least 2 consecutive years of data for analysis from July 1996 through June 1999 were identified. RESULTS: Children did not consistently meet the HEDIS criteria for persistent asthma, and 24% to 28% of children did not requalify in year 2 of observation. Multivariate regression models showed that a protective relationship between controller medication dispensing and asthma-related emergency department visits was no longer seen among children meeting the HEDIS criteria for persistent asthma when the total period of observation is extended to 2 years (odds ratio, 0.7; 95% confidence interval, 0.4-1.2). CONCLUSIONS: Our results suggest that the variable nature of asthma may affect how the HEDIS performance measure should be used for assessing quality of care. The period between identification of the target population and performance assessment should be closely related in time.

Variation in total and specific IgE: effects of ethnicity and socioeconomic status.

BACKGROUND: Asthma is common in minority and disadvantaged populations, whereas atopic disorders other than asthma appear to be less prevalent. It is unclear whether the same holds true for objective markers of sensitization. OBJECTIVE: To determine the association of asthma, atopic disorders, and specific sensitization with race and socioeconomic factors. METHODS: We analyzed total and specific IgE among 882 women (577 white, 169 black, and 136 Hispanic) who delivered a child at a large tertiary hospital in Boston, Mass, and who were screened for participation in a family and birth cohort study. Race/ethnicity and other characteristics were obtained from screening questionnaires. Addresses were geocoded, and 3 census-based geographic area socioeconomic variables were derived from block group information from the 1990 US Census. RESULTS: Black and Hispanic women were more likely to come from areas with low socioeconomic indicators and were more likely to have asthma than white women. However, these women were less likely to have hay fever and eczema than their white counterparts. Compared with white women, black women had higher mean total IgE levels; had greater proportions of sensitization to indoor, outdoor, and fungal allergens; and were more than twice as likely to be sensitized to > or =3 aeroallergens. CONCLUSION: The racial/ethnic disparities in atopic disorders may represent either underdiagnosis or underreporting and suggest that allergy testing may be underused in some populations. Differences in total IgE levels and specific allergen sensitization are likely a result of the complex interplay between exposures associated with socioeconomic disadvantage.

A multisite randomized trial of the effects of physician education and organizational change in chronic-asthma care: health outcomes of the Pediatric Asthma Care Patient Outcomes Research Team II Study.

BACKGROUND: Traditional primary care practice change approaches have not led to full implementation of national asthma guidelines. OBJECTIVE: To evaluate the effectiveness of 2 asthma care improvement strategies in primary care. DESIGN: Two-year randomized controlled clinical trial. SETTING: Forty-two primary care pediatric practices affiliated with 4 managed care organizations. PARTICIPANTS: Children aged 3 to 17 years with mild to moderate persistent asthma enrolled in primary care practices affiliated with managed care organizations. INTERVENTIONS: Peer leader education consisted of training 1 physician per practice in asthma guidelines and peer teaching methods. Planned care combined the peer leader program with nurse-mediated organizational change through planned visits with assessments, care planning, and self-management support, in collaboration with physicians. Analyses compared each intervention with usual care. MAIN OUTCOME MEASURES: Annualized asthma symptom days, asthma-specific functional health status (Children's Health Survey for Asthma), and frequency of brief oral steroid courses (bursts). RESULTS: Six hundred thirty-eight children completed baseline evaluations, representing 64% of those screened and eligible. Mean +/- SD age was 9.4 +/- 3.5 years; 60% were boys. Three hundred fifty (55%) were taking controller medication. Mean +/- SD annualized asthma symptom days was 107.4 +/- 122 days. Children in the peer leader arm had 6.5 fewer symptom days per year (95% confidence interval [CI], - 16.9 to 3.6), a nonsignificant difference, but had a 36% (95% CI, 11% to 54%) lower oral steroid burst rate per year compared with children receiving usual care. Children in the planned care arm had 13.3 (95% CI, - 24.7 to -2.1) fewer symptom days annually (-12% from baseline; P =.02) and a 39% (95% CI, 11% to 58%) lower oral steroid burst rate per year relative to usual care. Both interventions showed small, statistically significant effects for 2 of 5 Children's Health Survey for Asthma scales. Planned care subjects had greater controller adherence (parent report) compared with usual care subjects (rate ratio, 1.05 [95% CI, 1.00 to 1.09]). CONCLUSIONS: Planned care (nurse-mediated organizational change plus peer leader education) is an effective model for improving asthma care in the primary care setting. Peer leader education on its own may also serve as a useful model for improving asthma care, although it is less comprehensive and the treatment effect less pronounced.

Evaluation of asthma prescription measures and health system performance based on emergency department utilization.

BACKGROUND: Measures based on the use of either antiinflammatory and/or reliever medications have been used to evaluate clinical performance in asthma. OBJECTIVE: We compared the association between 2 asthma prescription measures (APMs) and subsequent risk of emergency department (ED) asthma visits. DESIGN: We conducted a cross-sectional analysis of automated pharmacy and healthcare utilization data from 3 large geographically diverse managed care organizations. PARTICIPANTS: We studied children, 3 to 15 years of age, with at least 1 encounter for asthma (hospitalization, ED, or ambulatory care), at least 1 dispensing of an asthma medication, and continuous enrollment between June 1996 and July 1997. MEASURES: Two performance measures were derived for patients with persistent asthma: 1) the proportion of individuals who have received controller therapy and 2) the ratio of dispensed controller to dispensed reliever medications. Children with persistent asthma were identified using the Health Employers Data Information System (HEDIS) criteria of the National Committee on Quality Assurance definition. Multivariate logistic regression was used to assess independent effects in models for ED visits. RESULTS: Among children with persistent asthma, the dispensing of a controller was associated with a significantly lower risk of an ED visit as compared with children not dispensed a controller (odds ratio, 0.3; 95% confidence interval, 0.2-0.4). An association between the ratio of controller to reliever dispensing and the risk of subsequent ED visit was also observed, however, the underlying level of reliever dispensing modified the relationship. Among children with persistent asthma, the ratio of controller to reliever dispensing was inversely associated with risk of ED visit among children dispensed <4 relievers/person-year but no significant relationship was seen among children dispensed > or =4 relievers/person-year. CONCLUSION: Among children with persistent asthma, the use of an asthma prescription measure (APM) can help stratify children based on their risk of future adverse events. The HEDIS measure, the dispensing of a controller medication among a population with persistent asthma, and the controller to reliever ratio are associated with the risk of subsequent ED visit. However, the association between the ratio measure and risk for ED visit is modified by the underlying level of reliever dispensing.

The burden of asthma in the United States: level and distribution are dependent on interpretation of the national asthma education and prevention program guidelines.

Asthma imposes a growing burden on society in terms of morbidity, quality of life, and healthcare costs. Although federally sponsored national surveys provide estimates of asthma prevalence, these surveys are not designed to characterize the burden of asthma by self-reported disease activity. We sought to characterize asthma burden in the United States. This study was based on a cross-sectional random-digit-dial household telephone survey designed to identify adult patients and parents of children with current asthma. Global asthma burden was comprised of three components: short-term symptom burden (4-week recall), long-term symptom burden (past year), and functional impact (activity limitation). Using this construct, only 10.7% of individuals were classified as having a global asthma burden consistent with mild intermittent disease, and 77.3% had moderate to severe persistent disease. These results suggest that a majority of the United States population with asthma experiences persistent rather than intermittent asthma burden. In addition, the discordance in type and distribution of asthma symptoms reported by individual subjects suggests that the exact estimate of the burden of asthma is related to how the National Asthma Education and Prevention Program classification is operationalized. Inquiry into recent day or nighttime symptoms alone underestimates the burden of asthma and may lead to inadequate treatment of asthma based on national guideline recommendations.