Diagnosis, testing, treatment, and outcomes among patients with advanced non-small cell lung cancer in the United States.

INTRODUCTION: Characteristics of patients in clinical trials may differ from those of real-world patients. Our objective was to describe biomarker testing and outcomes among patients with advanced non-small cell lung cancer (aNSCLC) in a real-world setting. METHODS: This retrospective cohort study included patients ≥18 years old, diagnosed with stage IIIB/C or IV NSCLC, and in the TEMPUS oncology dataset from January 1, 2012, to December 31, 2020. Patient characteristics associated with biomarker testing were evaluated in patients with positive biomarkers using univariate logistic regression models. Cox proportional hazard models were used to estimate median survival. RESULTS: Of 9540 patients included, 41.7% had biomarker testing, and 2158 had a positive biomarker result. Men (vs women; odds ratio [OR], 0.82; 95% CI: 0.74-0.91), Black patients (vs White; OR, 0.83; 95% CI: 0.72-0.97), patients with squamous (OR, 0.22; 95% CI: 0.19-0.25) or unknown histology (OR, 0.53; 95% CI: 0.45-0.61) (vs non-squamous histology), and patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2+ (OR, 0.69; 95% CI: 0.57-0.84) or missing (OR, 0.56; 95% CI: 0.48-0.66) (vs ECOG PS of 0) were less likely to undergo biomarker testing. Patients with positive biomarkers who received NCCN-recommended treatment options (55.7%) had significantly longer median overall survival (OS) (hazard ratio [HR], 0.84; 95% CI: 0.75-0.95) and real-world progression-free survival (rwPFS) (HR, 0.68; 95% CI: 0.62-0.75). CONCLUSION: More than 50% of patients were untested for biomarkers. Patients who were less likely to be tested included men, Black patients, current smokers, patients with squamous aNSCLC, and patients with an ECOG PS of 2+. Patients with positive biomarkers who received NCCN-recommended treatment options had significantly longer OS and PFS.

Systematic evidence-based review: The application of noninvasive prenatal screening using cell-free DNA in general-risk pregnancies.

PURPOSE: Noninvasive prenatal screening (NIPS) using cell-free DNA has been assimilated into prenatal care. Prior studies examined clinical validity and technical performance in high-risk populations. This systematic evidence review evaluates NIPS performance in a general-risk population. METHODS: Medline (PubMed) and Embase were used to identify studies examining detection of Down syndrome (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies, rare autosomal trisomies, copy number variants, and maternal conditions, as well as studies assessing the psychological impact of NIPS and the rate of subsequent diagnostic testing. Random-effects meta-analyses were used to calculate pooled estimates of NIPS performance (P < .05). Heterogeneity was investigated through subgroup analyses. Risk of bias was assessed. RESULTS: A total of 87 studies met inclusion criteria. Diagnostic odds ratios were significant (P < .0001) for T21, T18, and T13 for singleton and twin pregnancies. NIPS was accurate (≥99.78%) in detecting sex chromosome aneuploidies. Performance for rare autosomal trisomies and copy number variants was variable. Use of NIPS reduced diagnostic tests by 31% to 79%. Conclusions regarding psychosocial outcomes could not be drawn owing to lack of data. Identification of maternal conditions was rare. CONCLUSION: NIPS is a highly accurate screening method for T21, T18, and T13 in both singleton and twin pregnancies.

Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: To develop an evidence-based clinical practice guideline for the use of exome and genome sequencing (ES/GS) in the care of pediatric patients with one or more congenital anomalies (CA) with onset prior to age 1 year or developmental delay (DD) or intellectual disability (ID) with onset prior to age 18 years. METHODS: The Pediatric Exome/Genome Sequencing Evidence-Based Guideline Work Group (n = 10) used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) framework based on the recent American College of Medical Genetics and Genomics (ACMG) systematic review, and an Ontario Health Technology Assessment to develop and present evidence summaries and health-care recommendations. The document underwent extensive internal and external peer review, and public comment, before approval by the ACMG Board of Directors. RESULTS: The literature supports the clinical utility and desirable effects of ES/GS on active and long-term clinical management of patients with CA/DD/ID, and on family-focused and reproductive outcomes with relatively few harms. Compared with standard genetic testing, ES/GS has a higher diagnostic yield and may be more cost-effective when ordered early in the diagnostic evaluation. CONCLUSION: We strongly recommend that ES/GS be considered as a first- or second-tier test for patients with CA/DD/ID.

Gaucher disease type 1 patients from the ICGG Gaucher Registry sustain initial clinical improvements during twenty years of imiglucerase treatment.

BACKGROUND: Alglucerase enzyme replacement therapy was approved for Gaucher disease (GD) in the United States in 1991; imiglucerase in 1994. We report hematologic, visceral, bone pain, bone crisis, height, weight, and Body Mass Index (BMI) outcomes in patients treated for 20 (±3) years with subset analyses based on pre-treatment severity, genotype, and age at treatment initiation. METHODS: GD type 1 (GD1) patients in the ICGG Gaucher Registry with complete sets of baseline, 10-year, and 20-year data are included (N = 475). Ten-year and 20-year data are compared to pre-treatment baseline, stratified by splenectomy status. RESULTS: Non-splenectomized patients: Improvements observed at 10 years were maintained at 20 years for most outcomes. Mean changes from baseline at 10 and 20 years, respectively, were: spleen volume: 18.2 multiples of normal (MN) to 5.1 MN and 4.2 MN; liver volume: 1.8 MN to 1.0 MN and 1.0 MN; hemoglobin: 11.4 g/dL to 13.7 g/dL and 13.8 g/dL; platelet count: 91.6 × 109/L to 168.0 × 109/L and 169.1 × 109/L; without bone crisis: 85.0% to 98.2% and 96.5%; without bone pain: 52.5% to 72.0% at 10 years, no significant change at 20 years (58.5%). Splenectomized patients: significant changes were observed in liver volume: 2.3 MN to 1.1 MN and 1.0 MN; hemoglobin: 11.7 g/dL to 13.3 g/dL and 13.4 g/dL; platelet count: 229.1 × 109/L to 288.1 × 109/L and 257.0 × 109/L; without bone crisis: 52.2% to 91.3% and 100%; without bone pain: 16.3% to 30.6% (not significant) and 46.9%. Similar results were found in each of the subset analyses. Patients who start treatment during childhood have normal weight and height in young adulthood. Many treated adult patients are overweight or obese; however, this is consistent with BMI trends observed in the general population. After 1-2 years, the average biweekly imiglucerase dose is ~40 units/kg body weight. CONCLUSION: Imiglucerase is an effective, long-term treatment for GD1. In a long-term observational setting, improvements seen during early treatment years are sustained by continuing treatment for 20 years, except for bone pain in non-splenectomized patients. These results are consistent when analyzed by different patient subsets, including by disease severity.

Real-world effectiveness of eliglustat in treatment-naïve and switch patients enrolled in the International Collaborative Gaucher Group Gaucher Registry.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (90% of patients). We report real-world outcomes after 2 years of eliglustat therapy in the International Collaborative Gaucher Group Gaucher Registry (NCT00358943). As of January 2019, baseline and 2-year data (±1 year) were available for 231 eliglustat-treated GD1 patients: 19 treatment-naïve (zero splenectomized) and 212 ERT patients who switched to eliglustat (36 splenectomized). Most patients (89%) were from the United States, where eliglustat was first approved. In treatment-naïve patients, mean hemoglobin increased from 12.4 to 13.4 g/dL (P = .004, n = 18), mean platelet count increased from 113 to 156 × 109 /L (P < .001, n = 17); mean spleen volume decreased from 7.4 to 3.5 multiples of normal (MN) (P = .02, n = 7); mean liver volume remained normal (n = 7), and median spine Z-score was unchanged (-1.3 to -1.2, n = 6). In non-splenectomized switch patients, mean hemoglobin remained stable/non-anemic (n = 167); mean platelet count remained stable/normal (n = 165); mean spleen volume decreased from 3.3 to 2.8 MN (P < .001, n = 64); mean liver volume remained normal (n = 63), and median lumbar spine Z-score improved from -0.7 to -0.4 (P = .014, n = 68). In splenectomized switch patients, mean hemoglobin remained stable/non-anemic (n = 31); mean platelet count increased from 297 to 324 × 109 /L (non-significant, n = 29); mean liver volume remained normal (n = 13); median spine Z-score improved from -0.8 to -0.6 (non-significant, n = 11). Median chitotriosidase decreased in all groups (P < .01 for all). These real-world results are consistent with eliglustat clinical trial results demonstrating long-term benefit in treatment-naïve patients and stability in ERT switch patients.

Using State Birth Defects Registries to Evaluate Regional Critical Congenital Heart Disease Newborn Screening.

BACKGROUND: Most states have now passed legislation mandating pulse oximetry for all newborns, or have promulgated regulations or guidelines to encourage use of routine pulse oximetry. State-based birth defects registries may be well positioned to track and evaluate critical congenital heart disease (CCHD) screening coverage and outcomes. This purpose of this study was to determine: (1) the proportion of cases detected by screening, (2) health services use by children with CCHDs during the first year of life, and (3) mortality outcomes. METHODS: Records of children born in 2012 to 2013 with any of seven CCHD lesions were identified in New England birth defects databases. Information was abstracted from each child's medical record. Descriptive statistics were used to report results. RESULTS: From nearly 160,000 live births, 208 CCHD diagnoses were noted in the records of 157 children. Screening was noted in 67% of records of confirmed cases of CCHDs. Data completeness varied by state; for example, information was available regarding prenatal diagnosis in 91% of records and age at first surgery in 85% among states with active surveillance compared with 35% and 75%, respectively, with passive surveillance. Documentation of screening results in medical records was inconsistent. The one year survival was 85% (77/91). CONCLUSION: Birth defects surveillance systems can provide information on outcomes for infants with CCHDs. However, information varies by surveillance method and by hospital practices. Engaging hospitals in standardizing recording procedures and enhancing training and quality control could increase the value of birth defects registries records in assessing outcomes for children identified through CCHD screening. Birth Defects Research 109:1414-1422, 2017.© 2017 Wiley Periodicals, Inc.

Critical Congenital Heart Disease Newborn Screening Implementation: Lessons Learned.

Introduction The purpose of this article is to present the collective experiences of six federally-funded critical congenital heart disease (CCHD) newborn screening implementation projects to assist federal and state policy makers and public health to implement CCHD screening. Methods A qualitative assessment and summary from six demonstration project grantees and other state representatives involved in the implementation of CCHD screening programs are presented in the following areas: legislation, provider and family education, screening algorithms and interpretation, data collection and quality improvement, telemedicine, home and rural births, and neonatal intensive care unit populations. Results The most common challenges to implementation include: lack of uniform legislative and statutory mandates for screening programs, lack of funding/resources, difficulty in screening algorithm interpretation, limited availability of pediatric echocardiography, and integrating data collection and reporting with existing newborn screening systems. Identified solutions include: programs should consider integrating third party insurers and other partners early in the legislative/statutory process; development of visual tools and language modification to assist in the interpretation of algorithms, training programs for adult sonographers to perform neonatal echocardiography, building upon existing newborn screening systems, and using automated data transfer mechanisms. Discussion Continued and expanded surveillance, research, prevention and education efforts are needed to inform screening programs, with an aim to reduce morbidity, mortality and other adverse consequences for individuals and families affected by CCHD.

Prevalence and reasons for delaying and foregoing necessary care by the presence and type of disability among working-age adults.

BACKGROUND: While it is commonly accepted that disparities in unmet need for care vary by age, race/ethnicity, income, education, and access to care, literature documenting unmet needs experienced by adults with different types of disabilities is developing. OBJECTIVE: The main objective was to determine whether subgroups of people with disabilities are more likely than people without disabilities to delay/forgo necessary care, in general and among the insured. METHODS: We used pooled Medical Expenditure Panel Survey data (2004-2010) to examine delaying or forgoing medical, dental, and pharmacy care among five disability subgroups (physical, cognitive, visual, hearing, multiple) and the non-disabled population. Logistic regression was conducted to examine delayed/forgone care, controlling for sociodemographic, health, and health care factors. RESULTS: Over 13% of all working-age adults delayed/forwent necessary care; lack of insurance was the strongest predictor of unmet needs. Among the insured, disability subgroups were greater than two times more likely to report delayed/forgone care than adults without disabilities. Insured working-age adults with multiple chronic conditions and those with ADL/IADL assistance needs had higher odds of delayed or forgone care than their peers without these characteristics. Reasons related to affordability were most often listed as leading to unmet needs, regardless of disability. CONCLUSION: Although insurance status most strongly predicted unmet needs for care, many people with insurance delayed/forewent necessary care. Even among the insured, all disability subgroups had significantly greater likelihood of having to delay/forgo care than those without disabilities. Differences also existed between the disability subgroups. Cost was most frequently cited reason for unmet needs.

Asthma and asthma-related health care utilization among people without disabilities and people with physical disabilities.

BACKGROUND: Previous research has shown that people with disabilities have higher rates of some chronic diseases and receive poorer disease-specific care than their counterparts without disabilities. Yet, little is known about the relationship between asthma and disability. OBJECTIVE: This study examines whether differences in the prevalence of asthma, asthma flare, and asthma-related measures of health care quality, utilization and cost exist among people with physical limitations (PL) and without any limitations. METHODS: Data from the 2004-2010 Medical Expenditure Panel Survey were pooled to compare outcomes for working-age adults (18-64) with PL to those with no limitations. RESULTS: People with PL had higher rates of asthma (13.8% vs. 5.9%, p < 0.001) and recent asthma flare (52.6% vs. 39.6%, p < 0.001) than people without limitations. There were no differences in health care quality, utilization or cost between people with PL and people without limitations in multivariate analyses. CONCLUSIONS: Although there are no differences in asthma-related quality or utilization of health care, people with PL have poorer asthma control than people without limitations. Research is needed to determine what factors (e.g., focus on other acute ailments, perceptions that asthma control cannot improve) are related to this outcome. Future research must also examine differences in asthma severity, and its impact on asthma control and health care-related outcomes, among people with and without disabilities.

National Survey of Providers Treating Patients With Metabolic Disorders Identified by Newborn Screening Demonstrates Challenges Faced by Clinical Care Systems.

OBJECTIVES: To evaluate care processes for infants who are identified by newborn screening (NBS) and diagnosed with metabolic disorders during their first year of life. METHODS: A survey instrument was used to assess the scope and intensity of services needed to provide quality health care for patients from birth to 1 year of age who have a metabolic disorder identified by NBS. Significance testing was not performed; descriptive analyses are reported. RESULTS: Providers spend significant amounts of time on activities that are not direct patient care. The most challenging aspect of their work was the lack of reimbursement for care. CONCLUSION: Provision of genetics services for patients with a metabolic disorder is time and labor intensive, and insurance coverage and reimbursement for these services remain inadequate. Health care payment and/or system reform is necessary to provide optimal care to patients with metabolic disorders identified by NBS.

A survey of the preferences of primary care physicians regarding the comanagement with specialists of children with rare or complex conditions.

OBJECTIVES: To assess primary care pediatric providers' comfort with co-managing patients with rare conditions. METHODS: A survey was sent via an electronic link to pediatricians and family practitioners. Chi-square test of significance and Fisher's exact test were used for categorical variable comparisons and the Student's t test was used for continuous variable comparisons. RESULTS: Most of the providers believed that care decisions are most frequently made by the specialist with consultation with the primary care clinician. The most common source of information is direct communication from the specialist. The most effective tool to increase clarity and comfort about provider roles was an active care plan identifying current care needs, who will act on the plan, and when the action should be completed. CONCLUSIONS: Coordinated co-management in which caregiving roles are explicitly defined and tools are available for the timely exchange of information among all key participants warrants further study.

Thyroperoxidase and thyroglobulin antibodies in early pregnancy and placental abruption.

OBJECTIVE: To estimate the relationship between thyroid antibodies and placental abruption. METHODS: This cohort study assesses thyroperoxidase and thyroglobulin antibodies in relation to placental abruption among 10,062 women with singleton viable pregnancies (from the First and Second Trimester Risk of Aneuploidy [FaSTER] trial). A thyroperoxidase antibody cutoff of 50 international units/mL is used for comparison with published data from another cohort. RESULTS: Women with elevated thyroperoxidase antibody levels in the first and second trimesters have a higher rate of placental abruption than antibody-negative women. This relationship is less strong in the first trimester (1.51% compared with 0.83%; odds ratio [OR], 1.83; 95% confidence interval [CI], 0.99-3.37) than in the second trimester (1.78% compared with 0.82%; OR, 2.20; 95% CI, 1.21-3.99). A similar, but weaker, relationship is present for thyroglobulin antibodies. Sixty-four of 782 thyroperoxidase antibody-positive pregnancies without abruption become negative by the second trimester; one pregnancy with abruption becomes antibody-positive. Odds ratios for pregnancies with both thyroperoxidase and thyroglobulin antibody elevations are also higher (first trimester: OR, 2.10; 95% CI, 0.91-4.86; second trimester: OR, 2.73; 95% CI, 1.17-6.33). CONCLUSION: The present data confirm an association between thyroid antibody elevations and placental abruption described in a recent report. These findings, however, do not provide support for recommending routine testing for thyroid antibodies during pregnancy. LEVEL OF EVIDENCE: II.

Thyroperoxidase and thyroglobulin antibodies in early pregnancy and preterm delivery.

OBJECTIVE: To further evaluate the relationship between thyroid antibodies and preterm births. METHODS: This is a prospective study of pregnancy outcome and demographic data combined with retrospective measurement of thyroperoxidase and thyroglobulin antibodies. Sera were obtained at 11-13 and 15-18 weeks of gestation from 10,062 women with singleton viable pregnancies (a subset from the First- and Second-Trimester Risk of Aneuploidy [FaSTER] trial). RESULTS: Women with elevated levels of thyroperoxidase, thyroglobulin antibodies, or both in the first trimester have a higher rate of preterm delivery before 37 weeks of gestation than antibody-negative women (7.5% compared with 6.4%, odds ratio [OR] 1.18; 95% confidence interval [CI] 0.95-1.46). This is also the case for very preterm delivery before 32 weeks of gestation (1.2% compared with 0.7%, OR 1.70; 95% CI 0.98-2.94). Preterm premature rupture of membranes is also increased (2.0% compared with 1.2%, OR 1.67; 95% CI 1.05-2.44). These associations are less strong for second-trimester antibody measurements. CONCLUSION: The present data do not confirm strong associations between thyroid antibody elevations and preterm birth found in three of five previously published reports. Preterm premature rupture of membranes appears to contribute to the thyroid antibody-associated early deliveries, possibly as a result of inflammation. LEVEL OF EVIDENCE: II.

First- and second-trimester thyroid hormone reference data in pregnant women: a FaSTER (First- and Second-Trimester Evaluation of Risk for aneuploidy) Research Consortium study.

OBJECTIVE: The purpose of this study was to calculate first and second trimester reference ranges and within-woman correlations for TSH, free T4, and thyroid antibodies. STUDY DESIGN: TSH, free T4, and thyroid antibodies were measured in paired sera from 9562 women in the FaSTER trial of Down syndrome screening. RESULTS: The median first trimester TSH (1.05 mIU/L) is lower than the second (1.23 mIU/L); and 98th centile is higher (4.15 vs 3.77 mIU/L). Within-woman paired TSH correlations are moderately strong (r(2) = 0.64). Among women with first trimester TSH values above the 98th centile, second trimester values are over the 95th centile in 68%. Median first trimester free T4 values (1.10 ng/dL) are higher than second (1.01 ng/dL). Paired free T4 measurements correlate weakly (r(2) = 0.23). Among women with first trimester free T4 values below the 2nd centile, second trimester values are below the 5th centile in 32%. Antibody measurements correlate strongly between trimesters (thyroperoxidase r(2) = 0.79, thyroglobulin r(2) = 0.83). CONCLUSION: TSH and free T4 measurements require gestation-specific reference ranges.

Variability in thyroid-stimulating hormone suppression by human chorionic [corrected] gonadotropin during early pregnancy.

OBJECTIVE: The objective of the study was to further explore relationships between human chorionic gonadotropin (hCG), TSH, and free T4 in pregnant women at 11 through 18 wk gestation. STUDY DESIGN: The design of the study was to analyze hCG in comparison with TSH and free T4, in paired first- and second-trimester sera from 9562 women in the First and Second Trimester Evaluation of Risk for Fetal Aneuploidy trial study. RESULTS: hCG is strongly correlated with body mass index, smoking, and gravidity. Correlations with selected maternal covariates also exist for TSH and free T4. As hCG deciles increase, body mass index and percent of women who smoke both decrease, whereas the percent of primigravid women increases (P < 0.0001). hCG/TSH correlations are weak in both trimesters (r2 = 0.03 and r2 = 0.02). TSH concentrations at the 25th and fifth centiles become sharply lower at higher hCG levels, whereas 50th centile and above TSH concentrations are only slightly lower. hCG/free T4 correlations are weak in both trimesters (r2 = 0.06 and r2 = 0.003). At 11-13 wk gestation, free T4 concentrations rise uniformly at all centiles, as hCG increases (test for trend, P < 0.0001), but not at 15-18 wk gestation. Multivariate analyses with TSH and free T4 as dependent variables and selected maternal covariates and hCG as independent variables do not alter these observations. CONCLUSIONS: In early pregnancy, a woman's centile TSH level appears to determine susceptibility to the TSH being suppressed at any given hCG level, suggesting that hCG itself may be the primary analyte responsible for stimulating the thyroid gland. hCG affects lower centile TSH values disproportionately.

Sequential first- and second-trimester TSH, free thyroxine, and thyroid antibody measurements in women with known hypothyroidism: a FaSTER trial study.

OBJECTIVE: The purpose of this study was to examine how closely hypothyroidism management in the general pregnancy population satisfies recently issued guidelines and to determine whether improvements are indicated. STUDY DESIGN: This was an observational study in which women at 5 recruitment centers in the first- and second-trimester evaluation of risk for aneuploidy trial allowed the use of sequentially obtained first- and second-trimester sera for additional research. Three hundred eighty-nine women had hypothyroidism by self-report. Thyroid-related measurements were performed on all samples between July 2004 and May 2005. RESULTS: Forty-three percent of the thyroid-stimulating hormone (TSH) values are at or above recently recommended guidelines in the first trimester (2.5 mU/L), as opposed to 33% of the values in the second trimester (3.0 mU/L). Twenty percent of the TSH values are at or above a less restrictive 98th percentile of normal in the first trimester, as opposed to 23% of the values in the second trimester. Mean TSH levels are higher in women with antibodies. Free thyroxine values are unremarkable. CONCLUSION: Future strategies should focus on more effectively treating women with hypothyroidism who have persistently elevated TSH values.

Screen positive rates among six family history screening protocols for breast/ovarian cancer in four cohorts of women.

It has been estimated that approximately 2% of the general population has a family history that is indicative of hereditary breast/ovarian cancer. We aim to further document the proportions of women identified by several protocols as having a positive family history of breast/ovarian cancer, as a prelude to offering genetic counseling and BRCA1/2 mutation testing. This is a critical component of the evidence base needed when considering implementation of family history screening in primary care. We apply six separate family history screening protocols for breast/ovarian cancer to four cohorts of women, 21 to 55 years of age, for whom self-reported personal, and first and second degree family histories of breast/ovarian cancer have been obtained. We analyzed family history for 3,073 women in the four cohorts. The screen positive rates among the protocols vary widely both within and among the cohorts. In Cohort 4, the screen positive rate ranges between 6.9% to 20.8%, depending on the protocol. Applying one of the protocols to the four cohorts yields screen positive rates between 5.0% and 16.7%. The proportion of women that is screen positive on all six protocols (or three, if Ashkenazi Jewish) ranges from 1.9% to 4.0%. Used alone, none of the recommended family history protocols yields an acceptable screen positive rate. A more acceptable 2% to 4% screen positive rate can be expected when all six protocols agree.