Comparing the Centers for Medicare and Medicaid Services (CMS) enrollment data death dates to the National Death Index (NDI).

PURPOSE: In the United States, the National Death Index (NDI) is the most complete source of death information, while epidemiologic studies with mortality outcomes often rely on U.S. Medicare data for outcome ascertainment. The purpose of this study was to assess the agreement of death information between the Centers for Medicare & Medicaid Services (CMS) Medicare enrolment data and NDI. METHODS: Using Medicare and NDI data from 1999 through 2016, we identified Medicare beneficiaries who were reported dead in the CMS Medicare enrolment database (EDB) and Common Medicare Environment (CME), linked these beneficiaries to the NDI using CMS Health Insurance Claim number, and compared death dates between the two data sources. To assess agreement between our data sources, we calculated kappa scores; where a kappa of 1 indicates perfect agreement and a kappa of 0 indicates agreement equivalent to chance. We also examined CMS to NDI linkage and death date matching for stability over time. RESULTS: Of the 36 785 640, Medicare beneficiaries reported dead in CMS enrollment data from 1999 to 2016, 97.5% were linked to the NDI. A kappa score of 0.98 showed a near perfect agreement between NDI and CMS reported deaths. The percentage of linked cases exactly matching on death dates increased from 94.8% in 1999 to 99.4% in 2016. CONCLUSIONS: Our findings suggest strong concordance between death dates as recorded by CMS enrollment data and the NDI in the entire Medicare population.

Guillain-Barré Syndrome After High-Dose Influenza Vaccine Administration in the United States, 2018-2019 Season.

BACKGROUND: The Vaccine Safety Datalink (VSD) identified a statistical signal for an increased risk of Guillain-Barré syndrome (GBS) in days 1-42 after 2018-2019 high-dose influenza vaccine (IIV3-HD) administration. We evaluated the signal using Medicare. METHODS: We conducted early- and end-of-season claims-based self-controlled risk interval analyses among Medicare beneficiaries ages ≥65 years, using days 8-21 and 1-42 postvaccination as risk windows and days 43-84 as control window. The VSD conducted chart-confirmed analyses. RESULTS: Among 7 453 690 IIV3-HD vaccinations, we did not detect a statistically significant increased GBS risk for either the 8- to 21-day (odds ratio [OR], 1.85; 95% confidence interval [CI], 0.99-3.44) or 1- to 42-day (OR, 1.31; 95% CI, 0.78-2.18) risk windows. The findings from the end-of-season analyses were fully consistent with the early-season analyses for both the 8- to 21-day (OR, 1.64; 95% CI, 0.92-2.91) and 1- to 42-day (OR, 1.12; 95% CI, 0.70-1.79) risk windows. The VSD's chart-confirmed analysis, involving 646 996 IIV3-HD vaccinations, with 1 case each in the risk and control windows, yielded a relative risk of 1.00 (95% CI, 0.06-15.99). CONCLUSIONS: The Medicare analyses did not exclude an association between IIV3-HD and GBS, but it determined that, if such a risk existed, it was similar in magnitude to prior seasons. Chart-confirmed VSD results did not confirm an increased risk of GBS.

Comparison of propensity score methods for pre-specified subgroup analysis with survival data.

Examining medical products' benefits and risks in different population subsets is often necessary for informing public health decisions. In observational cohort studies, safety analyses by pre-specified subgroup can be powered, and are informative about different population subsets' risks if the study designs or analyses adequately control for confounding. However, few guidelines exist on how to simultaneously control for confounding and conduct subgroup analyses. In this simulation study, we evaluated the performance, in terms of bias, efficiency and coverage, of six propensity score methods in 24 scenarios by estimating subgroup-specific hazard ratios of average treatment effect in the treated with Cox regression models. The subgroup analysis methods control for confounding either by propensity score matching or by inverse probability treatment weighting. These methods vary as to whether they subset information or borrow it across subgroups to estimate the propensity score. Simulation scenarios varied by size of subgroup, strength of association of subgroup with exposure, strength of association of subgroup with outcome (simulated survival), and outcome incidence. Results indicated that subsetting the data by the subgrouping variable, to estimate the propensity score and hazard ratio, has the smallest bias, far exceeding any penalty in precision. Moreover, weighting methods pay a heavier price in bias than do matching methods when the propensity score model is misspecified and the subgrouping variable is a strong confounder.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Antihypertensive drug associated angioedema: effect modification by race/ethnicity.

PURPOSE: Assess angioedema risk with exposure to angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) compared with beta-blockers, by race/ethnicity. METHODS: New-user cohorts of Medicare beneficiaries 65 years or older initiating ACEI, ARB, or beta-blocker treatment from March 2007 to March 2014 were constructed. Angioedema incidence rates by drug and race/ethnicity were computed for 1-30 and 31-365 days of treatment. Cox proportional hazards regression was used to examine angioedema risk between cohorts. RESULTS: Angioedema incidence rates (per 1000 person years) in beta-blocker users were 1.80 (whites), 4.11 (blacks), 1.89 (Asians), and 2.10 (Hispanics); in ACEI users, 4.03, 23.77, 2.94, and 4.27; and in ARB users, 1.73, 3.11, 1.10, and 1.90, respectively. Incidence rates were significantly higher in the first 30 days of exposure for all drug × race/ethnic groups. Overall, angioedema risk increased among ACEI users (hazard ratio, 2.91; 95% confidence interval, 2.75-3.07) but not ARB users (0.93, 0.85-1.02) versus beta-blocker users. Angioedema risk with ACEIs versus beta-blockers increased more in blacks (6.28, 5.44-7.24) than whites (2.33, 2.19-2.48), Hispanics (2.04, 1.36-3.07), and Asians (1.48, 0.94-2.35). Compared with white beta-blocker users, angioedema risk was increased 2.9-fold in whites, 20.2-fold in blacks, and 2.3-fold in other race/ethnic groups combined during the first 30 days of ACEI exposure. CONCLUSIONS: There was significant effect modification of angioedema risk by race and ACEI use for blacks, but not for other race/ethnicity groups. Angioedema risk was significantly greater in the first 30 days of exposure for all, and highest among blacks.

CMPK1 and RBP3 are associated with corneal curvature in Asian populations.

Corneal curvature (CC) measures the steepness of the cornea and is an important parameter for clinically diseases such as astigmatism and myopia. Despite the high heritability of CC, only two associated genes have been discovered to date. We performed a three-stage genome-wide association study meta-analysis in 12 660 Asian individuals. Our Stage 1 was done in multiethnic cohorts comprising 7440 individuals, followed by a Stage 2 replication in 2473 Chinese and Stage 3 in 2747 Japanese. The SNP array genotype data were imputed up to the 1000 Genomes Project Phase 1 cosmopolitan panel. The SNP association with the radii of CC was investigated in the linear regression model with the adjustment of age, gender and principal components. In addition to the known genes, MTOR (also known as FRAP1) and PDGFRA, we discovered two novel genes associated with CC: CMPK1 (rs17103186, P = 3.3 × 10(-12)) and RBP3 (rs11204213 [Val884Met], P = 1.1 × 10(-13)). The missense RBP3 SNP, rs11204213, was also associated with axial length (AL) (P = 4.2 × 10(-6)) and had larger effects on both CC and AL compared with other SNPs. The index SNPs at the four indicated loci explained 1.9% of CC variance across the Stages 1 and 2 cohorts, while 33.8% of CC variance was explained by the genome-wide imputation data. We identified two novel genes influencing CC, which are related to either corneal shape or eye size. This study provides additional insights into genetic architecture of corneal shape.

Meta-analysis of genome-wide association studies in multiethnic Asians identifies two loci for age-related nuclear cataract.

Age-related cataract is a leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Previous linkage and candidate gene studies suggested genetic influences on age-related nuclear cataract but few genetic markers have been identified thus far. We conducted genome-wide association studies on 4569 Asians (including 2369 Malays and 2200 Indians), and replicated our analysis in 2481 Chinese from two independent cohorts (1768 Chinese in Singapore and 803 Chinese in Beijing). We confirmed two genome-wide significant loci for nuclear cataract in the combined meta-analysis of four cohorts (n = 7140). The first locus was at chromosome 3q25.31 in KCNAB1 (rs7615568, fixed-effect Pmeta = 2.30 × 10(-8); random-effect Pmeta = 1.08 × 10(-8)). The second locus was at chromosome 21 in the proximity of CRYAA (rs11911275, fixed-effect Pmeta = 2.77 × 10(-8); random-effect Pmeta = 1.98 × 10(-9)), a major protein component of eye lens. The findings were further supported by up-regulation and down-regulation of KCNAB1 and CRYAA in human lens capsule, respectively, as the severity of nuclear cataract increases. The results offer additional insights into the pathogenesis of nuclear cataract in Asians.

Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Glaucoma and associated visual acuity and field loss significantly affect glaucoma-specific psychosocial functioning.

OBJECTIVE: To examine the impact of glaucoma and visual acuity (VA) and visual field (VF) losses on psychosocial functioning (PF). DESIGN: Cross-sectional study. PARTICIPANTS: We compared PF between 192 participants with bilateral glaucoma with VA or VF losses and 40 controls from a tertiary eye hospital clinic in Singapore. METHODS: Glaucoma was defined using the Hodapp-Anderson-Parish criteria. Four psychosocial outcomes of the Glaucoma Quality of Life 36 questionnaire were psychometrically assessed using Rasch analysis. Multivariate regression was performed to determine the independent impact of glaucoma and VA and VF losses on PF. The impact of VA and VF on PF were evaluated by restricted cubic spline analysis. MAIN OUTCOME MEASURES: Anxiety, self-image, psychological well-being, and confidence in health care. RESULTS: The mean age of participants was 66.2±11.0 years, and 63% were male. In the better eye, VA and mean deviation were Snellen 20/25 and -8.89±6.52 dB, respectively. In multivariate models, glaucoma patients had 63.0% greater anxiety (95% confidence interval [CI], -66.0% to -61.2%; P<0.001), 71.0% lower self-image (95% CI, -74.1% to -68.5%; P<0.001), 38.3% less psychological well-being (95% CI, -37.4% to -39.0%; P<0.001), and 32.4% reduced confidence in health care than patients without glaucoma. The worst VA and VF categories had the most reduced PF (range, 26.0% to 81.5%; P<0.001 for all associations) compared with controls. With worsening VA, there was a linear increase in anxiety (P=0.009) and decrease in self-image (P=0.005). With worsening VF from 0 to -12.1 dB (P=0.003), anxiety increased before plateauing. Self-image decreased as VF worsened from 0 to -10 dB (P<0.001), and confidence in health care decreased when VF worsened from 0 to -9.3 dB (P=0.008). However, self-image and confidence in health care actually improved at greater levels of VF loss beyond these thresholds. CONCLUSION: Glaucoma negatively affects PF. Early stage glaucoma with mild VF loss adversely affects anxiety, self-image, and confidence in health care. As VA worsens in advanced glaucoma, anxiety further increases and self-image deteriorates. Ophthalmologists and glaucoma patients need to be aware that both VA and VF losses at different stages of glaucoma negatively impact PF.

Aggregate Effects of Intraocular Pressure and Cup-to-Disc Ratio Genetic Variants on Glaucoma in a Multiethnic Asian Population.

PURPOSE: High intraocular pressure (IOP) and large vertical cup-to-disc ratio (VCDR) are important risk factors of glaucoma. Recent genome-wide association studies have discovered several genetic variants associated with IOP and VCDR. In this study, we examined the aggregate effects of these IOP-, VCDR-associated variants on glaucoma. DESIGN: Case-control genetic association study. PARTICIPANTS: A total of 6881 participants, including 194 glaucoma and 158 primary open-angle glaucoma (POAG) cases in the Singapore Epidemiology of Eye Diseases Study. METHODS: We first identified IOP and VCDR risk single nucleotide polymorphisms (SNPs) that were located in previously discovered IOP, VCDR genetic loci and showed strongest associations with IOP and VCDR in our study. We then constructed multi-locus IOP-, VCDR-specific genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on glaucoma. Associations between tertiles of IOP- and VCDR-specific GRSs with glaucoma and POAG were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Odds ratios on glaucoma. RESULTS: Participants in the top tertile of IOP-specific GRS were 2.00 (95% CI, 1.32-3.03, P = 1.1×10(-3)) and 2.50 times (95% CI, 1.54-4.02, P = 2.0×10(-4)) likely to have glaucoma and POAG, respectively, compared with those in the bottom. Participants in the top tertile of VCDR-specific GRS were 2.09 (95% CI, 1.43-3.07, P = 1.6×10(-4)) and 2.31 times (95% CI, 1.50-3.55, P = 1.4×10(-4)) likely to have glaucoma and POAG, respectively. Participants with both GRSs in the top tertile were 5.54 (95% CI, 2.57-11.93, P = 1.1×10(-5)) and 7.77 times (95% CI, 3.03-19.93, P = 2.0×10(-5)) likely to have glaucoma and POAG, respectively, compared with participants with both GRSs in bottom tertiles. The GRSs improved AUC for glaucoma modestly when added to traditional factors (AUC difference = 0.03, P = 0.06). CONCLUSIONS: Higher IOP-, VCDR-specific GRSs were associated with greater risk of glaucoma. Participants with both GRSs in the top tertiles had a 5.5-fold increased risk of glaucoma compared with those in the bottom tertiles. These findings may provide insights into the genetic pathogenesis of glaucoma.

Ethnic differences of intraocular pressure and central corneal thickness: the Singapore Epidemiology of Eye Diseases study.

PURPOSE: To determine the ethnic differences in the distribution of intraocular pressure (IOP) and central corneal thickness (CCT) in a multi-ethnic Asian population by self-reported ethnicity and genetic ancestry. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 10 033 adults (3353 Chinese, 3280 Malays, and 3400 Indians) aged >40 years. METHODS: Participants underwent standardized systemic and ocular examinations and interviewer-administered questionnaires for risk factor assessment. The IOP readings were obtained by Goldmann applanation tonometry (Haag-Streit, Konig, Switzerland) before pupil dilation. The CCT was measured with ultrasound pachymetry. Genetic ancestry was derived using principal component (PC) analysis. Regression models were used to investigate the association of IOP and CCT with potential risk factors and genetic ancestry. MAIN OUTCOME MEASURES: Intraocular pressure and CCT. RESULTS: After excluding participants with a history of glaucoma surgery or medication, refractive surgery, corneal edema, or corneal dystrophy, IOP and CCT readings were available for 3251 Chinese, 3232 Malays, and 3317 Indians. The mean IOP readings in the Chinese, Malay, and Indian participants were 14.3±3.1, 15.3±3.7, and 15.8±2.9 mmHg, respectively (P < 0.001). The prevalence of participants with IOP ≥21 mmHg was 2.6% in Chinese, 6.2% in Malays, and 4% in Indians (P < 0.001). In the multivariate regression analysis, the Malay and Indian participants on average had 0.81 and 1.43 mmHg higher IOP levels, respectively, than Chinese (P < 0.001). The mean CCT reading was 552.3±33.4 µm in Chinese, 540.9±33.6 µm in Malays, and 540.4±33.6 µm in Indians (P < 0.001). The percentage of participants with CCT <555 µm was 52.8% in Chinese, 68.5% in Malays, and 66.2% in Indians (P < 0.001). The IOP and CCT levels are significantly correlated with genetic ancestry in our South East Asian population. CONCLUSIONS: Chinese have the thickest CCT but lowest IOP among the 3 major ethnic groups. In addition, there is a higher proportion of Malays with IOP ≥21 mmHg and CCT <555 µm compared with the Chinese or Indians. This disparity across ethnic groups should be taken into account by future studies investigating IOP and CCT as risk factors or diagnostic tests for glaucoma in Asian populations.

Pretreatment anterior segment imaging during acute primary angle closure: insights into angle closure mechanisms in the acute phase.

OBJECTIVE: To describe anterior segment optical coherence tomography (ASOCT) parameters during acute primary angle closure (APAC) before therapeutic interventions and comparative analyses of biometric parameters of APAC eyes with fellow eyes. DESIGN: Prospective, comparative case series. PARTICIPANTS: Thirty-one consecutive patients with APAC. METHODS: All patients underwent ASOCT imaging of both eyes during the attack, before therapeutic interventions were administered. Custom software was used to measure anterior chamber depth (ACD), anterior chamber area (ACA), anterior chamber volume (ACV), iris curvature (I-Curv), iris area (I-Area), lens vault (LV), and angle opening distance (AOD750), trabecular iris space area (TISA750), and iris thickness (IT750) at 750 µm from the scleral spur. Multivariate logistic regression modeling using forward selection was used to determine the most important biometric variables associated with APAC compared with the fellow eye during the attack. MAIN OUTCOME MEASURES: Anterior segment biometric parameters associated with APAC. RESULTS: The mean age of the patients was 60.9±7.5 years, and 11 patients (35.5%) were male. The mean intraocular pressure was 3.8±9.2 mmHg in the APAC eye and 4.2±4.3 mmHg in the fellow eye before treatment (P <0.001). After adjustment for pupil diameter, APAC eyes had smaller ACD, ACA, ACV, I-Curv (all P <0.001), AOD750 (P = 0.037), TISA750 (P = 0.043), I-Area (P = 0.027), and IT750 (P = 0.002) and larger LV (P = 0.041) than fellow eyes. An optimal model consisting of 3 variables (pupil diameter, ACD, and I-Curv) explained 36.7% of the variance in APAC occurrence, with ACD accounting for 18.1% and I-Curv accounting for 14.1% of this variance. CONCLUSIONS: Shallower ACD and smaller I-Curv were the 2 main anterior segment biometric parameters associated with APAC during the attack. These findings present new insights into the anterior segment biometric parameters of APAC and fellow eyes before therapeutic interventions. Anatomic changes in the anterior segment explained only about one third of the variance in APAC occurrence, and the role of nonanatomic factors require further investigation.

Assessment of iris surface features and their relationship with iris thickness in Asian eyes.

PURPOSE: To assess iris surface features in Asian eyes and examine their associations with iris thickness measured by anterior segment optical coherence tomography (AS OCT). DESIGN: Cross-sectional study. PARTICIPANTS: We recruited 250 subjects from the Singapore Malay Eye Study. METHODS: We obtained standardized slit-lamp photographs and developed a grading system assessing iris crypts (by number and size), furrows (by number and circumferential extent), and color (higher grade denoting darker iris). Vertical and horizontal cross-sections of the anterior chamber were imaged using AS OCT. Intragrader and intergrader agreements in the grading of iris surface were assessed by weighted κ (κ(w)) statistic. Associations of the average iris thickness with the grade of iris features were assessed using linear regression analysis. MAIN OUTCOME MEASURES: Frequency and size of iris crypts, furrows, and color; iris thickness at 750 µm (IT750) and 2000 µm (IT2000) from the scleral spur; and maximum iris thickness (ITM) averaged from the 4 quarters. RESULTS: Three hundred sixty-four eyes had complete and gradable data for crypts and color; 330 eyes were graded for furrows. The grading scheme showed good intragrader (crypt κ(w) = 0.919, furrow κ(w) =0.901, color κ(w) = 0.925) and intergrader (crypt κ(w) = 0.775, furrow κ(w) = 0.836, color κ(w) = 0.718) agreements. Higher crypt grade was associated independently with thinner IT750 (ß [change in iris thickness per grade higher] = -0.007; P = 0.029), IT2000 (ß = -0.018; P < 0.001), and ITM (ß = -0.012; P < 0.001). More extensive furrows were associated with thicker IT750 (ß = 0.022; P < 0.001). Darker iris was also associated with thicker IT750 (ß = 0.014; P = 0.001). CONCLUSIONS: Iris surface features, assessed and measured from slit-lamp photographs, correlate well with iris thickness. Irises with more crypts are thinner; irises with more extensive furrows and darker color are thicker peripherally. These findings may provide another means to assess angle closure risk based on iris features.

Body mass index and preclinical kidney disease in Indian adults aged 40 years and above without chronic kidney disease.

BACKGROUND: Obesity is associated with diabetes and hypertension, two major risk factors for chronic kidney disease (CKD). Recently, it has been shown that obesity is associated with preclinical kidney disease defined by elevated levels of cystatin C among those without CKD in US adults. However, the association of obesity with cystatin C is not known in industrialized Asian populations. METHODS: We examined 2,052 Indian adults aged 40-80 years in Singapore who were free of CKD defined as a serum creatinine-based estimated glomerular filtration rate (eGFRcr) <60 mL/min/1.73 m(2) and/or the presence of microalbuminuria. Body mass index (BMI) values were categorized into normal (18.5-24.9), overweight (25-29.9) and obese (≥30 kg/m(2)). Elevated serum cystatin C was defined as cystatin C ≥1 mg/L. RESULTS: Overweight and obesity were significantly associated with elevated levels of cystatin C after adjusting for potential confounders including diabetes and hypertension and eGFRcr. Compared to those with normal weight, the odds ratio (95 % confidence interval) of elevated cystatin C was 1.49 (1.17-1.88) for overweight and 3.20 (2.33-4.39) for obese. This association was consistently present when BMI was analyzed as a continuous variable and also in subgroups of men, women and in those without diabetes mellitus or hypertension. CONCLUSIONS: Higher BMI levels are associated with preclinical kidney disease in Indian adults aged 40 years and above without CKD.

Assessment of bony nasolacrimal parameters among Asians.

PURPOSE: A case series evaluating racial differences in the nasolacrimal region and quantifying the anterior lacrimal crest thickness and minimum nasolacrimal duct diameter in Asians. METHODS: Facial or orbital CT scans of 90 consecutive patients were retrospectively reviewed. Evidence of lacrimal fossa tumor or trauma excluded a patient. Using 3-dimensional image software, the thickness of the anterior lacrimal crest, narrowest diameter of the nasolacrimal duct, vertical diameter of the lacrimal sac fossa, frontonasal angle, and inter-frontozygomatic suture distance were measured in axial, sagittal, and coronal planes. RESULTS: Inter- and intraobserver correlation of a sample data proved reliability via intraclass correlation coefficient (0.706-0.917). Southeast Asians had a wider inter-frontozygomatic suture distance than South Asian and Occidental races (p = 0.025). Vertical lacrimal fossa diameter, anterior lacrimal crest thickness, and narrowest nasolacrimal duct diameter did not differ significantly between right and left sides or among ethnic groups. Narrower nasolacrimal duct diameter was significantly associated with decreased inter-frontozygomatic suture distance (p < 0.001), namely in patients with narrower faces. The anterior lacrimal crest thickness was significantly affected by the nasal configuration and thicker in patients with more acute frontonasal angle (p = 0.026). CONCLUSIONS: There is no significant difference in nasolacrimal duct diameter among ethnic groups, which may predispose one to nasolacrimal duct obstruction. But, this is significantly associated with inter-frontozygomatic suture distance, suggesting that a wider face is associated with wider nasolacrimal duct diameter. An acute frontonasal angle predicts a thicker anterior lacrimal crest for surgical preparation during dacryocystorhinostomy.

Real-world clinical and economic outcomes for patients with advanced non-small cell lung cancer enrolled in a clinical trial following comprehensive genomic profiling via liquid biopsy.

BACKGROUND: Oncology clinical trial enrollment is strongly recommended for patients with cancer who are not eligible for established and approved therapies. Many trials are specific to biomarker-targeted therapies, which are typically managed as specialty pharmacy services. Comprehensive genomic profiling (CGP) of advanced cancers has been shown to detect biomarkers, guide targeted treatment, improve outcomes, and result in the clinical trial enrollment of patients, which is modeled to offset pharmacy costs experienced by US payers, yet payer policy coverage remains inconsistent. A common concern limiting coverage of CGP by payers is the potential of identifying biomarkers beyond guideline-recommended treatments, which creates a perception that insurance companies are being positioned to "pay for research." However, these biomarkers can increase clinical trial eligibility, and specialty pharmacy management may have an interest in maximizing the clinical trial enrollment of members. OBJECTIVE: To investigate if clinical trial enrollment following liquid biopsy CGP for non-small cell lung cancer (NSCLC) is clinically and/or economically impactful from a payer claims perspective. METHODS: Clinical and economic outcomes were studied using a real-world clinical genomic database (including payer claims data) from patients with NSCLC who enrolled in clinical trials immediately following liquid biopsy CGP (using Guardant360) and matched NSCLC patient controls also tested with liquid biopsy CGP. RESULTS: Real-world overall survival was significantly (log-rank P < 0.0001) better for patients enrolled in clinical trials with similar costs of care, albeit with more outpatient encounters among those enrolled compared with matched controls. CONCLUSIONS: The results, together with previous analyses, suggest that, in addition to the clinical benefits associated with targeted therapies directed by CGP and other testing approaches, payers and specialty pharmacy managers may consider clinical trial direction and enrollment as a clinical and economic benefit of liquid biopsy CGP and adopt this into coverage decision frameworks and formularies.

Pan-Cancer Prevalence of Microsatellite Instability-High (MSI-H) Identified by Circulating Tumor DNA and Associated Real-World Clinical Outcomes.

PURPOSE: Immune checkpoint inhibitors are approved for advanced solid tumors with microsatellite instability-high (MSI-H). Although several technologies can assess MSI-H status, detection and outcomes with circulating tumor DNA (ctDNA)-detected MSI-H are lacking. As such, we examined pan-cancer MSI-H prevalence across 21 cancers and outcomes after ctDNA-detected MSI-H. METHODS: Patients with advanced cancer who had ctDNA testing (Guardant360) from October 1, 2018, to June 30, 2022, were retrospectively assessed for prevalence. GuardantINFORM, which includes anonymized genomic and structured payer claims data, was queried to assess outcomes. Patients who initiated new treatment within 90 days of MSI-H detection were sorted into immunotherapy included in treatment (IO) or no immunotherapy included (non-IO) groups. Real-world time to treatment discontinuation (rwTTD) and real-world time to next treatment (rwTTNT) were assessed in months as proxies of progression-free survival (PFS); real-world overall survival (rwOS) was assessed in months. Cox regression tests analyzed differences. Colorectal cancer, non-small-cell lung cancer (NSCLC), prostate cancer, gastroesophageal cancer, and uterine cancer (UC) were assessed independently; all other cancers were grouped. RESULTS: In total, 1.4% of 171,881 patients had MSI-H detected. Of 770 patients with outcomes available, rwTTD and rwTTNT were significantly longer for patients who received IO compared with non-IO for all cancers (P ≤ .05; hazard ratio [HR] range, 0.31-0.52 and 0.25-0.54, respectively) except NSCLC. rwOS had limited follow-up for all cohorts except UC (IO 39 v non-IO 23 months; HR, 0.18; P = .004); however, there was a consistent trend toward prolonged OS in IO-treated patients. CONCLUSION: These data support use of a well-validated ctDNA assay to detect MSI-H across solid tumors and suggest prolonged PFS in patients treated with IO-containing regimens after detection. Tumor-agnostic, ctDNA-based MSI testing may be reliable for rapid decision making.

Real-World Clinical Outcomes after Genomic Profiling of Circulating Tumor DNA in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer.

Comprehensive genomic profiling for advanced non-small cell lung cancer (NSCLC) can identify patients for molecularly targeted therapies that improve clinical outcomes. We analyzed data from 3084 patients (median age 65 years, 72.9% with adenocarcinoma) with advanced NSCLC registered in a real-world healthcare claims database (GuardantINFORMTM, Guardant Health) who underwent next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) testing (Guardant360®, Guardant Health) after first-line therapy (28.0% with agents targeted against genomic alterations). ctDNA was detected in 2771 samples (89.9%), of which 41.9% harbored actionable alterations, most commonly EGFR (epidermal growth factor receptor) mutations (29.7%). Actionable alterations were detected in 26.7% of patients (534/2001) previously treated with non-targeted agents. Emerging potentially targetable mutations were found in 40.1% (309/770) of patients previously treated with targeted therapies. Among patients with qualifying alterations detected by ctDNA testing, the time to treatment discontinuation (median 8.8 vs. 4.2 months; hazard ratio 1.97, p < 0.001) and overall survival (median 36.1 vs. 16.6 months; hazard ratio 2.08, p < 0.001) were longer for those who received matched second-line therapy versus unmatched second-line therapy. In real-world practice, results of a blood-based NGS assay prior to second-line treatment inform therapeutic decisions that can improve clinical outcomes for patients with advanced NSCLC.

Comprehensive Genomic Profiling of Circulating Tumor DNA in Patients with Previously Treated Metastatic Colorectal Cancer: Analysis of a Real-World Healthcare Claims Database.

We used a real-world database (GuardantINFORMTM) to analyze the treatment choices for patients with mCRC who underwent next-generation sequencing of circulating tumor DNA (ctDNA) using a commercially available test (Guardant360®) after first- or second-line therapy. From 18,875 patients with claims for CRC, 1064 had confirmed metastatic disease and sufficient histories for analysis (median age 59 years, 44.8% female, 44.5% left-sided). ctDNA was detectable for 997/1064 (93.7%) patients. Clinically actionable molecular profiles were present for 507/1064 (47.7%) patients, including those who had not received targeted therapy in the previous line (410/926, 44.3%). Second- or third-line targeted therapies were administered to 338/1064 patients (31.8%) and were considered matched for 193/338 (57.1%) patients. Therapies administered after testing were informed by the ctDNA results in 56.7% of patients overall (603/1064). Time to treatment discontinuation was most favorable for patients with a clinically actionable ctDNA profile who received matched therapy. This analysis demonstrates the real-world clinical value of plasma-based comprehensive genomic profiling for selecting appropriate molecular-targeted therapies in mCRC patients with disease progression after first- or second-line therapy.

Mortality Among Parkinson's Disease Patients Treated With Pimavanserin or Atypical Antipsychotics: An Observational Study in Medicare Beneficiaries.

OBJECTIVE: Pimavanserin, a serotonin 5-HT2 antagonist, is indicated for treatment of hallucinations and delusions associated with Parkinson's disease psychosis. In premarketing trials in patients with Parkinson's disease psychosis, 11% of patients died during open-label pimavanserin treatment. Antipsychotics, which are used off-label in Parkinson's disease psychosis, increase mortality in dementia patients. The authors compared mortality with pimavanserin and atypical antipsychotics in a large database. METHODS: This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW). RESULTS: Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients. CONCLUSIONS: Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.