Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.

BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. CONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).

Estimands, Handling of Missing Data and Impact on Assumed Effect Size and Power in Pivotal COVID-19 Treatment Trials.

Estimands play an important role for aligning study objectives, study design and analyses through a precise definition of the quantity of interest. For COVID-19 studies, apart from intercurrent events, high volume of missing data has been observed. We explore their impact on several estimands through a synthetic COVID-19 data generated from a discrete-time multi-state model. We compare estimators of these estimands based on their ability to closely match the true response rates and retain assumed power. The final choice of the estimand then needs to be aligned with clinically meaningful quantities of interest to patients, clinicians, regulators and payers.

Inverse probability weighted estimators of vaccine effects accommodating partial interference and censoring.

Estimating population-level effects of a vaccine is challenging because there may be interference, that is, the outcome of one individual may depend on the vaccination status of another individual. Partial interference occurs when individuals can be partitioned into groups such that interference occurs only within groups. In the absence of interference, inverse probability weighted (IPW) estimators are commonly used to draw inference about causal effects of an exposure or treatment. Tchetgen Tchetgen and VanderWeele proposed a modified IPW estimator for causal effects in the presence of partial interference. Motivated by a cholera vaccine study in Bangladesh, this paper considers an extension of the Tchetgen Tchetgen and VanderWeele IPW estimator to the setting where the outcome is subject to right censoring using inverse probability of censoring weights (IPCW). Censoring weights are estimated using proportional hazards frailty models. The large sample properties of the IPCW estimators are derived, and simulation studies are presented demonstrating the estimators' performance in finite samples. The methods are then used to analyze data from the cholera vaccine study.

Win ratio approach for analyzing composite time-to-event endpoint with opposite treatment effects in its components.

There is an increasing interest in the use of win ratio with composite time-to-event due to its flexibility in combining component endpoints. Exploring this flexibility further, one interesting question is in assessing the impact when there is a difference in treatment effect in the component endpoints. For example, the active treatment may prolong the time to occurrence of the negative event such as death or ventilation; meanwhile, the treatment effect may also shorten the time to achieving positive events, such as recovery or improvement. Notably, this portrays a situation where the treatment effect on time to recovery is in a different direction of benefit compared to the time to ventilation or death. Under such circumstances, if a single endpoint is used, the benefit gained for other individual outcomes is not counted and is diminished. As consequence, the study may need a larger sample size to detect a significant effect of treatment. Such a scenario can be handled by win ratio in a novel way by ranking component events, which is different from the usual composite endpoint approach such as time-to-first event. To evaluate how the different directions of treatment effect on component endpoints will impact the win ratio analysis, we use a Clayton copula-based bivariate survival simulation to investigate the correlation of component time-to-event. Through simulation, we found that compared to the marginal model using single endpoints, the win ratio analysis on composite endpoint performs better, especially when the correlation between two events is weak. Then, we applied the methodology to an infectious disease progression simulated study motivated by COVID-19. The application demonstrates that the win ratio approach offers advantages in empirical power compared to the traditional Cox proportional hazard approach when there is a difference in treatment effect in the marginal events.

Targeting physical activity interventions for adults: When should intervention occur?

Understanding demographic differences in transitions across physical activity (PA) levels is important for informing PA-promoting interventions, yet few studies have examined these transitions in contemporary multi-ethnic adult populations. We estimated age-, race/ethnicity-, and sex-specific 1-year net transition probabilities (NTPs) for National Health and Nutrition Examination Survey (2007-2012, n=11,556) and Hispanic Community Health Study/Study of Latinos (2008-2011, n=15,585) adult participants using novel Markov-type state transition models developed for cross-sectional data. Among populations with ideal PA (≥150min/week; ranging from 56% (non-Hispanic black females) to 88% (non-Hispanic white males) at age 20), NTPs to intermediate PA (>0-<149min/week) generally increased with age, particularly for non-Hispanic black females for whom a net 0.0% (95% confidence interval (CI): 0.0, 0.2) transitioned from ideal to intermediate PA at age 20; by age 70, the NTP rose to 3.6% (95% CI: 2.3, 4.8). Heterogeneity in intermediate to poor (0min/week) PA NTPs also was observed, with NTPs peaking at age 20 for Hispanic/Latino males and females [age 20 NTP=3.7% (95% CI: 2.0, 5.5) for females and 5.0% (1.2, 8.7) for males], but increasing throughout adulthood for non-Hispanic blacks and whites [e.g. age 70 NTP=7.8% (95% CI: 6.1, 9.6%) for black females and 8.1% (4.7, 11.6) for black males]. Demographic differences in PA net transitions across adulthood justify further development of tailored interventions. However, innovative efforts may be required for populations in which large proportions have already transitioned from ideal PA by early adulthood.

Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial.

BACKGROUND: Weight reduction is a standard recommendation for obstructive sleep apnea (OSA) treatment in people with obesity or overweight; however, weight loss can be challenging to achieve and maintain without bariatric surgery. Currently, no approved anti-obesity medication has demonstrated effectiveness in OSA management. This study is evaluating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA in people with obesity. METHODS: SURMOUNT-OSA, a randomized, placebo -controlled, 52-week phase 3 trial, is investigating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA (apnea hypopnea- index ≥15 events/h) in participants with obesity (body mass index ≥30 kg/m2) and an established OSA diagnosis. SURMOUNT-OSA is made of 2 intervention-specific appendices (ISAs): ISA-1 includes participants with no current OSA treatment, and ISA-2 includes participants using positive airway pressure therapy. Overall, 469 participants have been randomized 1:1 to receive tirzepatide or placebo across the master protocol (ISA-1, n = 234; ISA-2, n = 235). All participants are also receiving lifestyle intervention for weight reduction. RESULTS: The primary endpoint for the individual ISAs is the difference in apnea hypopnea- index response, as measured by polysomnography, between tirzepatide and placebo arms at week 52. Secondary endpoints include sleep apnea-specific hypoxic burden, functional outcomes, and cardiometabolic biomarkers. The trial employs digital wearables, including home sleep testing to capture time to improvement and accelerometry for daily physical activity assessment, to evaluate exploratory outcomes. CONCLUSION: SURMOUNT-OSA brings a novel design to investigate if tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting the underlying etiology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05412004.

Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial.

BACKGROUND: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. METHODS: This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31-0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33-0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups. INTERPRETATION: In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings. FUNDING: Eli Lilly and Company.

Baricitinib and primary biliary cholangitis.

BACKGROUND AND AIMS: There is an unmet need for alternative treatments for patients with primary biliary cholangitis (PBC) who do not respond to treatment with ursodeoxycholic acid (UDCA). A proof-of-concept study of baricitinib, an orally administered Janus kinase 1 and 2 inhibitor, was initiated to evaluate its use in PBC patients. APPROACH AND RESULTS: Patients with PBC showing inadequate response or intolerance to UDCA were eligible. This was a randomized, double-blinded placebo-controlled trial. Enrollees were assigned 1:1 to baricitinib (2 mg/day) or placebo. Endpoints included change in alkaline phosphatase (ALP), itch Numeric Rating Score (NRS), and fatigue NRS at 12 weeks post-baseline; exploratory markers included high sensitivity C-reactive protein (hs-CRP) and Enhanced Liver Fibrosis (ELF) score.Due to low enrollment, the study was terminated early. Two patients were enrolled and completed the trial; 1 was randomized to receive baricitinib and 1 to placebo. Over the treatment period, the baricitinib-treated patient demonstrated a 30% decrease in ALP and a 7-point improvement in the itch NRS, but a 2-point increase in the Fatigue NRS. Markers of inflammation and liver fibrosis (hs-CRP and ELF score) also improved over the study period. In contrast, the placebo-treated patient showed no improvement in primary or secondary endpoints. A single non-serious treatment-emergent adverse event of moderate sinusitis was reported by the baricitinib-treated patient at day 47. CONCLUSIONS: In a 12-week trial, a patient with PBC showing inadequate response to treatment with UDCA demonstrated a dramatic response to treatment with baricitinib.

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. METHODS: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. INTERPRETATION: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. FUNDING: Eli Lilly and Company. TRANSLATIONS: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Transitions from Ideal to Intermediate Cholesterol Levels may vary by Cholesterol Metric.

To examine the ability of total cholesterol (TC), a low-density lipoprotein cholesterol (LDL-C) proxy widely used in public health initiatives, to capture important population-level shifts away from ideal and intermediate LDL-C throughout adulthood. We estimated age (≥20 years)-, race/ethnic (Caucasian, African American, and Hispanic/Latino)-, and sex- specific net transition probabilities between ideal, intermediate, and poor TC and LDL-C using National Health and Nutrition Examination Survey (2007-2014; N = 13,584) and Hispanic Community Health Study/Study of Latinos (2008-2011; N = 15,612) data in 2016 and validated and calibrated novel Markov-type models designed for cross-sectional data. At age 20, >80% of participants had ideal TC, whereas the race/ethnic- and sex-specific prevalence of ideal LDL-C ranged from 39.2%-59.6%. Net transition estimates suggested that the largest one-year net shifts away from ideal and intermediate LDL-C occurred approximately two decades earlier than peak net population shifts away from ideal and intermediate TC. Public health and clinical initiatives focused on monitoring TC in middle-adulthood may miss important shifts away from ideal and intermediate LDL-C, potentially increasing the duration, perhaps by decades, that large segments of the population are exposed to suboptimal LDL-C.

Author Correction: Transitions from Ideal to Intermediate Cholesterol Levels may vary by Cholesterol Metric.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Heterogeneity in Blood Pressure Transitions Over the Life Course: Age-Specific Emergence of Racial/Ethnic and Sex Disparities in the United States.

Importance: Many studies have assessed racial/ethnic and sex disparities in the prevalence of elevated blood pressure (BP) from childhood to adulthood, yet few have examined differences in age-specific transitions between categories of BP over the life course in contemporary, multiracial/multiethnic populations. Objective: To estimate age, racial/ethnic, and sex-specific annual net transition probabilities between categories of BP using Markov modeling of cross-sectional data from the National Health and Nutrition Examination Survey. Design, Setting, and Participants: National probability sample (National Health and Nutrition Examination Survey in 2007-2008, 2009-2010, and 2011-2012) of 17 747 African American, white American, and Mexican American participants aged 8 to 80 years. The data were analyzed from September 2014 to November 2015. Main Outcomes and Measures: Age-specific American Heart Association-defined BP categories. Results: Three National Health and Nutrition Examination Survey cross-sectional samples were used to characterize the ages at which self-reported African American (n = 4973), white American (n = 8886), and Mexican American (n = 3888) populations transitioned between ideal BP, prehypertension, and hypertension across the life course. At age 8 years, disparities in the prevalence of ideal BP were observed, with the prevalence being lower among boys (86.6%-88.8%) compared with girls (93.0%-96.3%). From ages 8 to 30 years, annual net transition probabilities from ideal to prehypertension among male individuals were more than 2 times the net transition probabilities of their female counterparts. The largest net transition probabilities for ages 8 to 30 years occurred in African American young men, among whom a net 2.9% (95% CI, 2.3%-3.4%) of those with ideal BP transitioned to prehypertension 1 year later. Mexican American young women aged 8 to 30 years experienced the lowest ideal to prehypertension net transition probabilities (0.6%; 95% CI, 0.3%-0.8%). After age 40 years, ideal to prehypertension net transition probabilities stabilized or decreased (range, 3.0%-4.5%) for men, whereas net transition probabilities for women increased rapidly (range, 2.6%-13.0%). Mexican American women exhibited the largest ideal to prehypertension net transition probabilities after age 60 years. The largest prehypertension to hypertension net transition probabilities occurred at young ages in boys of white race/ethnicity and African Americans, approximately age 8 years and age 25 years, respectively, while net transition probabilities for white women and Mexican Americans increased over the life course. Conclusions and Relevance: Heterogeneity in net transition probabilities from ideal BP emerge during childhood, with associated rapid declines in ideal BP observed in boys and African Americans, thus introducing disparities. Primordial prevention beginning in childhood and into early adulthood is necessary to preempt the development of prehypertension and hypertension, as well as associated racial/ethnic and sex disparities.

Disparities in Early Transitions to Obesity in Contemporary Multi-Ethnic U.S. Populations.

BACKGROUND: Few studies have examined weight transitions in contemporary multi-ethnic populations spanning early childhood through adulthood despite the ability of such research to inform obesity prevention, control, and disparities reduction. METHODS AND RESULTS: We characterized the ages at which African American, Caucasian, and Mexican American populations transitioned to overweight and obesity using contemporary and nationally representative cross-sectional National Health and Nutrition Examination Survey data (n = 21,220; aged 2-80 years). Age-, sex-, and race/ethnic-specific one-year net transition probabilities between body mass index-classified normal weight, overweight, and obesity were estimated using calibrated and validated Markov-type models that accommodated complex sampling. At age two, the obesity prevalence ranged from 7.3% in Caucasian males to 16.1% in Mexican American males. For all populations, estimated one-year overweight to obesity net transition probabilities peaked at age two and were highest for Mexican American males and African American females, for whom a net 12.3% (95% CI: 7.6%-17.0%) and 11.9% (95% CI: 8.5%-15.3%) of the overweight populations transitioned to obesity by age three, respectively. However, extrapolation to the 2010 U.S. population demonstrated that Mexican American males were the only population for whom net increases in obesity peaked during early childhood; age-specific net increases in obesity were approximately constant through the second decade of life for African Americans and Mexican American females and peaked at age 20 for Caucasians. CONCLUSIONS: African American and Mexican American populations shoulder elevated rates of many obesity-associated chronic diseases and disparities in early transitions to obesity could further increase these inequalities if left unaddressed.

Reducing the Blood Pressure-Related Burden of Cardiovascular Disease: Impact of Achievable Improvements in Blood Pressure Prevention and Control.

BACKGROUND: US blood pressure reduction policies are largely restricted to hypertensive populations and associated benefits are often estimated based on unrealistic interventions. METHODS AND RESULTS: We used multivariable linear regression to estimate incidence rate differences contrasting the impact of 2 pragmatic hypothetical interventions to reduce coronary heart disease, stroke, and heart failure (HF) incidence: (1) a population-wide intervention that reduced systolic blood pressure by 1 mm Hg and (2) targeted interventions that reduced the prevalence of unaware, untreated, or uncontrolled blood pressure above goal (per Eighth Joint National Committee treatment thresholds) by 10%. In the Atherosclerosis Risk in Communities Study (n=15 744; 45 to 64 years at baseline, 1987-1989), incident coronary heart disease and stroke were adjudicated by physician panels. Incident HF was defined as the first hospitalization with discharge diagnosis code of "428." A 10% proportional reduction in unaware, untreated, or uncontrolled blood pressure above goal resulted in ≈4.61, 3.55, and 11.01 fewer HF events per 100,000 person-years in African Americans, and 3.77, 1.63, and 4.44 fewer HF events per 100 000 person-years, respectively, in whites. In contrast, a 1 mm Hg population-wide systolic blood pressure reduction was associated with 20.3 and 13.3 fewer HF events per 100 000 person-years in African Americans and whites, respectively. Estimated event reductions for coronary heart disease and stroke were smaller than for HF, but followed a similar pattern for both population-wide and targeted interventions. CONCLUSIONS: Modest population-wide shifts in systolic blood pressure could have a substantial impact on cardiovascular disease incidence and should be developed in parallel with interventions targeting populations with blood pressure above goal.

A quantile-based method for association mapping of quantitative phenotypes: an application to rheumatoid arthritis phenotypes.

Genetic association of population-based quantitative trait data has traditionally been analyzed using analysis of variance (ANOVA). However, violations of certain statistical assumptions may lead to false-positive association results. In this study, we have explored model-free alternatives to ANOVA using correlations between allele frequencies in the different quantile intervals of the quantitative trait and the quantile values. We performed genome-wide association scans on anti-cyclic citrullinated peptide and rheumatoid factor-immunoglobulin M, two quantitative traits correlated with rheumatoid arthritis, using the data provided in Genetic Analysis Workshop 16. Both the quantitative traits exhibited significant evidence of association on Chromosome 6, although not in the human leukocyte antigen region which is known to harbor a major gene predisposing to rheumatoid arthritis. We found that while a majority of the significant findings using the asymptotic thresholds of ANOVA was not validated using permutations, a relatively higher proportion of the significant findings using the asymptotic cut-offs of the correlation statistic were validated using permutations.