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Objectives: To assess whether the characteristics and capabilities of individual practices intending to join the early Medicare accountable care organization (ACO) programs differed from those of practices not intending to join., Study Design: Data from a 2012-2013 national survey of 1398 physician practices were linked to 2012 Medicare beneficiary claims data to examine differences between practices intending to join a Medicare ACO and practices not intending to join a Medicare ACO., Methods: Differences were examined with regard to patient sociodemographic characteristics and disease burden, practice characteristics and capabilities, and cost and quality measures. Logistic regression was used to examine the differences., Results: Practices intending to join were more likely to have better care management capabilities (odds ratio [OR], 1.72; P <.003), health information technology functionality (OR, 1.87; P <.001), and use of quality improvement methods (OR, 1.52; P <.04). They were also more likely to have had prior pay-for-performance experience (OR, 1.59; P <.02) and less likely to be physician-owned (OR, 0.51; P <.001). However, the practices with the greater capabilities still used half or less of them., Conclusions: Physician practices that intended to join the early ACO programs had greater capabilities and experience to manage risk than those practices that decided not to join. The early ACO programs thus attracted the more capable physician practices, but those practices still fell short of implementing key recommended behaviors. The findings have implications for future physician practice selection into ACOs.

Objective: To examine the relationship of physician versus hospital ownership of small- and medium-sized practices with spending and utilization of care., Data Source/study Setting/data Collection: Survey data for 1,045 primary care-based practices of 1-19 physicians linked to Medicare claims data for 2008 for 282,372 beneficiaries attributed to the 3,010 physicians in these practices., Study Design: We used generalized linear models to estimate the associations between practice characteristics and outcomes (emergency department visits, index admissions, readmissions, and spending)., Principal Findings: Beneficiaries linked to hospital-owned practices had 7.3 percent more emergency department visits and 6.4 percent higher total spending compared to beneficiaries linked to physician-owned practices., Conclusions: Physician practices are increasingly being purchased by hospitals. This may result in higher total spending on care., (© Health Research and Educational Trust.)

Objectives: To evaluate whether greater experience and success with performance incentives among physician practices are related to increased participation in Medicare's voluntary value-based payment reforms., Data Sources/study Setting: Publicly available data from Medicare's Physician Compare (n = 1,278; January 2012 to November 2013) and nationally representative physician practice data from the National Survey of Physician Organizations 3 (NSPO3; n = 907,538; 2013)., Study Design: We used regression analysis to examine practice-level relationships between prior exposure to performance incentives and participation in key Medicare value-based payment reforms: accountable care organization (ACO) programs, the Physician Quality Reporting System ("Physician Compare"), and the Meaningful Use of Health Information Technology program ("Meaningful Use"). Prior experience and success with financial incentives were measured as (1) the percentage of practices' revenue from financial incentives for quality or efficiency; and (2) practices' exposure to public reporting of quality measures., Data Collection/extraction Methods: We linked physician participation data from Medicare's Physician Compare to the NSPO3 survey., Principal Findings: There was wide variation in practices' exposure to performance incentives, with 64 percent exposed to financial incentives, 45 percent exposed to public reporting, and 2.2 percent of practice revenue coming from financial incentives. For each percentage-point increase in financial incentives, there was a 0.9 percentage-point increase in the probability of participating in ACOs (standard error [SE], 0.1, p < .001) and a 0.8 percentage-point increase in the probability of participating in Meaningful Use (SE, 0.1, p < .001), controlling for practice characteristics. Financial incentives were not associated with participation in Physician Compare. Among ACO participants, a 1 percentage-point increase in incentives was associated with a 0.7 percentage-point increase in the probability of being "very well" prepared to utilize cost and quality data (SE, 0.1, p < .001)., Conclusions: Physicians organizations' prior experience and success with performance incentives were related to participation in Medicare ACO arrangements and participation in the meaningful use criteria but not to participation in Physician Compare. We conclude that Medicare must complement financial incentives with additional efforts to address the needs of practices with less experience with such incentives to promote value-based payment on a broader scale., (© Health Research and Educational Trust.)

Background: The growing movement toward more accountable care delivery and the increasing number of people with chronic illnesses underscores the need for primary care practices to engage patients in their own care., Objective: For adult primary care practices seeing patients with diabetes and/or cardiovascular disease, we examined the relationship between selected practice characteristics, patient engagement, and patient-reported outcomes of care., Design: Cross-sectional multilevel observational study of 16 randomly selected practices in two large accountable care organizations (ACOs)., Participants: Patients with diabetes and/or cardiovascular disease (CVD) who met study eligibility criteria (n = 4368) and received care in 2014 were randomly selected to complete a patient activation and PRO survey (51% response rate; n = 2176). Primary care team members of the 16 practices completed surveys that assessed practice culture, relational coordination, and teamwork (86% response rate; n = 411)., Main Measures: Patient-reported outcomes included depression (PHQ-4), physical functioning (PROMIS SF12a), and social functioning (PROMIS SF8a), the Patient Assessment of Chronic Illness Care instrument (PACIC-11), and the Patient Activation Measure instrument (PAM-13). Patient-level covariates included patient age, gender, education, insurance coverage, limited English language proficiency, blood pressure, HbA1c, LDL-cholesterol, and disease comorbidity burden. For each of the 16 practices, patient-centered culture and the degree of relational coordination among team members were measured using a clinician and staff survey. The implementation of shared decision-making activities in each practice was assessed using an operational leader survey., Key Results: Having a patient-centered culture was positively associated with fewer depression symptoms (odds ratio [OR] = 1.51; confidence interval [CI] 1.04, 2.19) and better physical function scores (OR = 1.85; CI 1.25, 2.73). Patient activation was positively associated with fewer depression symptoms (OR = 2.26; CI 1.79, 2.86), better physical health (OR = 2.56; CI 2.00, 3.27), and better social health functioning (OR = 4.12; CI 3.21, 5.29). Patient activation (PAM-13) mediated the positive association between patients' experience of chronic illness care and each of the three patient-reported outcome measures-fewer depression symptoms, better physical health, and better social health. Relational coordination and shared decision-making activities reported by practices were not significantly associated with higher patient-reported outcome scores., Conclusions: Diabetic and CVD patients who received care from ACO-affiliated practices with more developed patient-centered cultures reported lower PHQ-4 depression symptom scores and better physical functioning. Diabetic and CVD patients who were more highly activated to participate in their care reported lower PHQ-4 scores and better physical and social outcomes of care.

Structural integration is increasing among medical groups, but whether these changes yield care that is more integrated remains unclear. We explored the relationships between structural integration characteristics of 144 medical groups and perceptions of integrated care among their patients. Patients' perceptions were measured by a validated national survey of 3,067 Medicare beneficiaries with multiple chronic conditions across six domains that reflect knowledge and support of, and communication with, the patient. Medical groups' structural characteristics were taken from the National Study of Physician Organizations and included practice size, specialty mix, technological capabilities, and care management processes. Patients' survey responses were most favorable for the domain of test result communication and least favorable for the domain of provider support for medication and home health management. Medical groups' characteristics were not consistently associated with patients' perceptions of integrated care. However, compared to patients of primary care groups, patients of multispecialty groups had strong favorable perceptions of medical group staff knowledge of patients' medical histories. Opportunities exist to improve patient care, but structural integration of medical groups might not be sufficient for delivering care that patients perceive as integrated., (Project HOPE—The People-to-People Health Foundation, Inc.)

Purpose: Implementation and meaningful use of health information technology (HIT) has been shown to facilitate delivery system transformation, yet implementation is far from universal. This study examined correlates of greater HIT implementation over time among a national cohort of small primary care practices in the United States., Methods: We used data from a 40-minute telephone panel survey of 566 small primary care practices having 8 or fewer physicians to investigate adoption and use of HIT in 2007-2010 and 2012-2013. We used generalized estimating equations (GEE) to estimate the association of practice characteristics and external incentives with the adoption and use of HIT. We studied 18 measures of HIT functionalities, including record keeping, clinical decision support, patient communication, and health information exchange with hospitals and pharmacies., Results: Overall, use of 16 HIT functionalities increased significantly over time, whereas use of 2 decreased significantly. On average, compared with physician-owned practices, hospital-owned practices used 1.48 (95% CI, 1.07-1.88; P <.001) more HIT processes. And relative to smaller practices, practices with 3 to 8 physicians used 2.49 (95% CI, 2.26-2.72; P <.001) more HIT processes. Participation in pay-for-performance programs, participation in public reporting of clinical quality data, and a larger proportion of revenue from Medicare were also associated with greater adoption and use of HIT., Conclusions: The new Medicare Access and CHIP Reauthorization Act (MACRA) will provide payment incentives and technical support to speed HIT adoption and use by small practices. We found that external incentives were, indeed, positively associated with greater adoption and use of HIT. Our findings also support a strategy of targeting assistance to smaller physician practices and those that are physician owned., (© 2017 Annals of Family Medicine, Inc.)

Unlabelled: Policy Points The rate of adoption of chronic care management processes (CMPs) by physician organizations has been fairly slow in spite of demonstrated effectiveness of CMPs in improving outcomes of chronic care. Exnovation (ie, removal of innovations) by physician organizations largely explains the slow population-level increases in practice use of CMPs over time. Expanded health information technology functions may aid practices in retaining CMPs. Low provider reimbursement by Medicaid programs, however, may contribute to disinvestment in CMPs by physician organizations., Context: Exnovation is the process of removal of innovations that are not effective in improving organizational performance, are too disruptive to routine operations, or do not fit well with the existing organizational strategy, incentives, structure, and/or culture. Exnovation may contribute to the low overall adoption of care management processes (CMPs) by US physician organizations over time., Methods: Three national surveys of US physician organizations, which included common questions about organizational characteristics, use of CMPs, and health information technology (HIT) capabilities for practices of all sizes, and Truven Health Insurance Coverage Estimates were integrated to assess organizational and market influences on the exnovation of CMPs in a longitudinal cohort of 1,048 physician organizations. CMPs included 5 strategies for each of 4 chronic conditions (diabetes, asthma, congestive heart failure, and depression): registry use, nurse care management, patient reminders for preventive and care management services to prevent exacerbations of chronic illness, use of nonphysician clinicians to provide patient education, and quality of care feedback to physicians., Findings: Over one-third (34.1%) of physician organizations exnovated CMPs on net. Quality of care data feedback to physicians and patient reminders for recommended preventive and chronic care were discontinued by over one-third of exnovators, while nurse care management and registries were largely retained. Greater proportions of baseline Medicaid practice revenue (incidence rate ratio [IRR] = 1.44, p < 0.001) and increasing proportions of revenue from Medicaid (IRR = 1.02, p < 0.05) were associated with greater CMP exnovation by physician organizations on net. Practices with greater expansion of HIT functionality exnovated fewer CMPs (IRR = 0.91, p < 0.001) compared to practices with less expansion of HIT functionality., Conclusions: Exnovation of CMPs is an important reason why the population-level adoption of CMPs by physician organizations has remained low. Expanded HIT functions and changes to Medicaid reimbursement and incentives may aid the retention of CMPs by physician organizations., (© 2016 Milbank Memorial Fund.)

Practice ownership and Medicaid revenue may affect the use of care management processes (CMPs) for chronic conditions and expansion of health information technology (HIT). Using a national cohort of medical practices, we compared the use of CMPs and HIT from 2006/2008 to 2013 by practice ownership and level of Medicaid revenue. Poisson regression models estimated changes in CMP use, and linear regression estimated changes in HIT, by practice ownership and Medicaid patient revenue, controlling for other practice characteristics. Compared with physician-owned practices, system-owned practices adopted a greater number of CMPs and HIT functions over time (p < .001). High Medicaid revenue (≥30.0%) was associated with less adoption of CMPs (p < .001) and HIT (p < .01). System-owned practices (p < .001) and community health centers (p < .001) with high Medicaid revenue were more likely than physician-owned practices with high Medicaid revenue to adopt CMPs over time. System and community health center ownership appear to help high Medicaid practices overcome CMP adoption constraints., (© The Author(s) 2015.)

Primary care physicians play an important role in the diagnosis and management of depression. Yet little is known about their use of care management processes for depression. Using national survey data for the period 2006-13, we assessed the use of five care management processes for depression and other chronic illnesses among primary care practices in the United States. We found significantly less use for depression than for asthma, congestive heart failure, or diabetes in 2012-13. On average, practices used fewer than one care management process for depression, and this level of use has not changed since 2006-07, regardless of practice size. In contrast, use of diabetes care management processes has increased significantly among larger practices. These findings may indicate that US primary care practices are not well equipped to manage depression as a chronic illness, despite the high proportion of depression care they provide. Policies that incentivize depression care management, including additional quality metrics, should be considered., (Project HOPE—The People-to-People Health Foundation, Inc.)

Introduction: Many patients who use tobacco have never been encouraged by their healthcare providers to quit. In recent years, incentives have been provided for medical practices to incorporate tobacco-cessation processes into routine care. This study examined growth in use of these processes as well as organizational and policy factors associated with their implementation., Methods: Data from three National Study of Physician Organizations surveys fielded in 2006-2013 were analyzed in 2014. The analyses estimated multivariate longitudinal and cross-sectional linear regression models to assess the relationship between implementation of cessation processes and change in practices' characteristics and external incentives, including state mandates for tobacco-cessation coverage., Results: Systematic identification of patients who use tobacco increased in large (26% to 91%, p<0.0001) and small-medium practices (69% to 83%, p<0.0001). Neither routine advice to quit nor referral to counseling and guideline-based point-of-care reminders increased. Practice feedback to physicians on their use of cessation interventions increased (18% to 29%, p<0.0001) for small-medium practices. State-mandated coverage was associated with the use of cessation processes in small-medium practices (p<0.0001), as was pay for performance participation (p<0.0001); public reporting (p<0.0001); Medicaid revenue (p=0.02); and practice size (p<0.0001). Among large practices, predictors were practice size (p<0.0001); hospital ownership (p=0.004); public reporting (p=0.03); and primary care practice (p=0.04)., Conclusions: The findings suggest that state-mandated coverage for tobacco-cessation treatment and increased use of external incentives such as pay for performance and public reporting programs may improve care for patients who use tobacco., (Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Reports suggest a trend for physician practices to change ownership from physicians to hospitals. It remains unclear how this change affects quality of patient care. We report the effect of a change to hospital ownership on the use of care management processes (CMPs) and health information technology (IT) among practices in the United States., Study Design: Trend analyses of 3 large national surveys of physician practices., Methods: We included 2 cohorts of practices: large practices with 20 or more physicians and small/medium practices with fewer than 20 physicians. The main outcomes were the changes in CMP and health IT indices among practices that were acquired by hospitals. We used multivariate logistic regression to assess these changes., Results: Large practices acquired by hospitals had larger increases in their CMP index than those that remained physician-owned (11.0-point increase vs 7.0-point decrease; adjusted P = .03). Small/medium practices acquired by hospitals had smaller but significantly higher increases in their CMP score (3.8 points vs 2.6 points; adjusted P = .04). Among all practices, there were no significant differences in the change of the health IT index., Conclusions: We found a significant increase in the use of CMPs among practices that were acquired by hospitals and no difference in health IT use. These findings suggest that a trend for hospitals to own physician practices may have a positive effect on chronic disease management and quality of care.

To improve health care quality within communities, increasing numbers of multistakeholder alliances-groups of payers, purchasers, providers, and consumers-have been created. We used data from two rounds (conducted in July 2007-March 2009 and January 2012-November 2013) of a large nationally representative survey of small and medium-size physician practices. We examined whether the adoption of patient-centered medical home processes spread more rapidly in fourteen Robert Wood Johnson Foundation Aligning Forces for Quality communities, where multistakeholder health care alliances promoted their use, than in other communities. We found no difference in the overall growth of adoption of the processes between the two types of communities. However, improvement on a care coordination subindex was 7.17 percentage points higher in Aligning Forces for Quality communities than in others. Despite the enthusiasm for quality improvement led by multistakeholder alliances, such alliances may not be a panacea for spreading patient-centered medical home processes across a community., (Project HOPE—The People-to-People Health Foundation, Inc.)

Accountable care organizations (ACOs) have incentives to meet quality and cost targets to share in any resulting savings. Achieving these goals will require ACOs to engage more actively with patients and their families. The extent to which ACOs do so is currently unknown. Using mixed methods, including a national survey, phone interviews, and site-visits, we examine the extent to which ACOs actively engage patients and their families, explore challenges involved, and consider approaches for dealing with those challenges. Results indicate that greater ACO use of patient activation and engagement (PAE) activities at the point-of-care may be related to positive perceptions among ACO leaders of the impact of PAE investments on ACO costs, quality, and outcomes of care. We identify a number of important practices associated with greater PAE, including high-level leadership commitment, goal-setting supported by adequate resources, extensive provider training, use of interdisciplinary care teams, and frequent monitoring and reporting on progress., (© The Author(s) 2015.)

Background: The accountable care organization (ACO) is a new organizational form to manage patients across the continuum of care. There are numerous questions about how ACOs should be optimally structured, including compensation arrangements with primary care physicians., Methods: Using data from a national survey of physician practices, we compared primary care physicians' compensation between practices in ACOs and practices that varied in their financial risk for primary care costs using 3 groups: practices not participating in a Medicare ACO and with no substantial risk for primary care costs; practices not participating in an ACO but with substantial risk for primary care costs; and practices participating in an ACO regardless of their risk for primary care costs. We measured physicians' compensation as the percentage of compensation based on salary, productivity, clinical quality or patient experience, and other factors. Regression models estimated physician compensation as a function of ACO participation and risk for primary care costs while controlling for other practice characteristics., Results: Physicians in ACO and non-ACO practices with no substantial risk for costs on average received nearly one-half of their compensation from salary, slightly less from productivity, and about 5% from quality and other factors. Physicians not in ACOs but with substantial risk for primary care costs received two-thirds of their compensation from salary, nearly one-third from productivity, and slightly more than 1% from quality and other factors. Participation in ACOs was associated with significantly higher physician compensation for quality; however, participation was not significantly associated with compensation from salary, whereas financial risk was associated with much greater compensation from salary., Conclusion: Although practices in ACOs provide higher compensation for quality, compared with practices at large, they provide a similar mix of compensation based on productivity and salary. Incentives for ACOs may not be sufficiently strong to encourage practices to change physician compensation policies for better patient experience, improved population health, and lower per capita costs., (© 2015 Annals of Family Medicine, Inc.)

The effective management of patients with chronic illnesses is critical to bending the curve of health care spending in the United States and is a crucial test for health care reform. In this article we used data from three national surveys of physician practices between 2006 and 2013 to determine the extent to which practices of all sizes have increased their use of evidence-based care management processes associated with patient-centered medical homes for patients with asthma, congestive heart failure, depression, and diabetes. We found relatively large increases over time in the overall use of these processes for small and medium-size practices as well as for large practices. However, the large practices used fewer than half of the recommended processes, on average. We also identified the individual processes whose use increased the most and show that greater use of care management processes is positively associated with public reporting of patient experience and clinical quality and with pay-for-performance., (Project HOPE—The People-to-People Health Foundation, Inc.)

Objective: To provide the first nationally based information on physician practice involvement in ACOs., Data Sources/study Setting: Primary data from the third National Survey of Physician Organizations (January 2012-May 2013)., Study Design: We conducted a 40-minute phone survey in a sample of physician practices. A nationally representative sample of practices was surveyed in order to provide estimates of organizational characteristics, care management processes, ACO participation, and related variables for four major chronic illnesses., Data Collection/extraction Methods: We evaluated the associations between ACO participation, organizational characteristics, and a 25-point index of patient-centered medical home processes., Principal Findings: We found that 23.7 percent of physician practices (n = 280) reported joining an ACO; 15.7 percent (n = 186) were planning to become involved within the next 12 months and 60.6 percent (n = 717) reported no involvement and no plans to become involved. Larger practices, those receiving patients from an IPA and/or PHO, those that were physician-owned versus hospital/health system-owned, those located in New England, and those with greater patient-centered medical home (PCMH) care management processes were more likely to have joined an ACO., Conclusions: Physician practices that are currently participating in ACOs appear to be relatively large, or to be members of an IPA or PHO, are less likely to be hospital-owned and are more likely to use more care management processes than nonparticipating practices., (© Health Research and Educational Trust.)

Nearly two-thirds of US office-based physicians work in practices of fewer than seven physicians. It is often assumed that larger practices provide better care, although there is little evidence for or against this assumption. What is the relationship between practice size--and other practice characteristics, such as ownership or use of medical home processes--and the quality of care? We conducted a national survey of 1,045 primary care-based practices with nineteen or fewer physicians to determine practice characteristics. We used Medicare data to calculate practices' rate of potentially preventable hospital admissions (ambulatory care-sensitive admissions). Compared to practices with 10-19 physicians, practices with 1-2 physicians had 33 percent fewer preventable admissions, and practices with 3-9 physicians had 27 percent fewer. Physician-owned practices had fewer preventable admissions than hospital-owned practices. In an era when health care reform appears to be driving physicians into larger organizations, it is important to measure the comparative performance of practices of all sizes, to learn more about how small practices provide patient care, and to learn more about the types of organizational structures--such as independent practice associations--that may make it possible for small practices to share resources that are useful for improving the quality of care., (Project HOPE—The People-to-People Health Foundation, Inc.)

Background: Adverse socioeconomic position (SEP) in childhood and adulthood is associated with a proinflammatory phenotype, and therefore an important exposure to consider for multiple sclerosis (MS), a complex neuroinflammatory autoimmune disease. The objective was to determine whether SEP over the life course confers increased susceptibility to MS., Methods: 1643 white, non-Hispanic MS case and control members recruited from the Kaiser Permanente Medical Care Plan, Northern California Region, for which comprehensive genetic, clinical and environmental exposure data have been collected were studied. Logistic regression models investigated measures of childhood and adulthood SEP, and accounted for effects due to established MS risk factors, including HLA-DRB1*15:01 allele carrier status, smoking history, history of infectious mononucleosis, family history of MS and body size., Results: Multiple measures of childhood and adulthood SEP were significantly associated with risk of MS, including parents renting versus owning a home at age 10: OR=1.48, 95% CI 1.09 to 2.02, p=0.013; less than a college education versus at least a college education based on parental household: OR=1.28, 95% CI 1.01 to 1.63, p=0.041; low versus high life course SEP: OR=1.50, 95% CI 1.09 to 2.05, p=0.012; and low versus high social mobility: OR=1.74, 95% CI 1.27 to 2.39, p=5.7×10(-4)., Conclusions: Results derived from a population-representative case-control study provide support for the role of adverse SEP in MS susceptibility and add to the growing evidence linking lower SEP to poorer health outcomes. Both genetic and environmental contributions to chronic conditions are important and must be characterised to fully understand MS aetiology., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Pay-for-performance, public reporting, and accountable care organization programs place pressures on physicians to use health information technology and organized care management processes to improve the care they provide. But physician practices that are not large may lack the resources and size to implement such processes. We used data from a unique national survey of 1,164 practices with fewer than twenty physicians to provide the first information available on the extent to which independent practice associations (IPAs) and physician-hospital organizations (PHOs) might make it possible for these smaller practices to share resources to improve care. Nearly a quarter of the practices participated in an IPA or a PHO that accounted for a significant proportion of their patients. On average, practices participating in these organizations provided nearly three times as many care management processes for patients with chronic conditions as nonparticipating practices did (10.4 versus 3.8). Half of these processes were provided only by IPAs or PHOs. These organizations may provide a way for small and medium-size practices to systematically improve care and participate in accountable care organizations.

The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774(*)C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2 × 10(-3)). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5 × 10(-3)) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P(meta)=2.5 × 10(-4)). In all three analyses, the strongest evidence for association between rs4774(*)C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P(meta)=1.9 × 10(-3)). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor regulating genes required for human leukocyte antigen (HLA) class II MHC-restricted antigen presentation. MHC genes, particularly HLA class II, are strongly associated with risk of developing rheumatoid arthritis (RA). Given the strong biological relationship between CIITA and HLA class II genes, a comprehensive investigation of CIITA variation in RA was conducted. This study tested 31 CIITA single-nucleotide polymorphisms in 2542 RA cases and 3690 controls (N=6232). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for association between CIITA variation and RA was observed after a correction for multiple testing was applied. This is the largest study to fully characterize common genetic variation in CIITA, including an assessment of haplotypes. Results exclude even a modest role for common CIITA polymorphisms in susceptibility to RA.

CLEC16A, a putative immunoreceptor, was recently established as a susceptibility locus for type I diabetes and multiple sclerosis. Subsequently, associations between CLEC16A and rheumatoid arthritis (RA), Addison's disease and Crohn's disease have been reported. A large comprehensive and independent investigation of CLEC16A variation in RA was pursued. This study tested 251 CLEC16A single-nucleotide polymorphisms in 2542 RA cases (85% anti-cyclic citrullinated peptide (anti-CCP) positive) and 2210 controls (N=4752). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for significant association between CLEC16A variation and RA was observed. This is the first study to fully characterize common genetic variation in CLEC16A including assessment of haplotypes and gender-specific effects. The previously reported association between RA and rs6498169 was not replicated. Results show that CLEC16A does not have a prominent function in susceptibility to anti-CCP-positive RA.

Objective: Genetic susceptibility to systemic lupus erythematosus (SLE) is well established, with the HLA class II DRB1 and DQB1 loci demonstrating the strongest association. However, HLA may also influence SLE through novel biologic mechanisms in addition to genetic transmission of risk alleles. Evidence for increased maternal-offspring HLA class II compatibility in SLE and differences in maternal versus paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen [NIMA] effects) in other autoimmune diseases have been reported. Thus, we investigated maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 in SLE., Methods: The cohort comprised 707 SLE families and 188 independent healthy maternal-offspring pairs (total of 2,497 individuals). Family-based association tests were conducted to compare transmitted versus nontransmitted alleles (transmission disequilibrium test) and both maternally versus paternally transmitted (parent-of-origin) and nontransmitted alleles (using the chi-square test of heterogeneity). Analyses were stratified according to the sex of the offspring. Maternally affected offspring DRB1 compatibility in SLE families was compared with paternally affected offspring compatibility and with independent control maternal-offspring pairs (using Fisher's test) and was restricted to male and nulligravid female offspring with SLE., Results: As expected, DRB1 was associated with SLE (P < 1 x 10(-4)). However, mothers of children with SLE had similar transmission and nontransmission frequencies for DRB1 alleles when compared with fathers, including those for the known SLE risk alleles HLA-DRB1*0301, *1501, and *0801. No association between maternal-offspring compatibility and SLE was observed., Conclusion: Maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 are unlikely to play a role in SLE.

The MHC class II transactivator gene (CIITA) is an important transcription factor regulating gene required for HLA class II MHC-restricted antigen presentation. Association with HLA class II variation, particularly HLA-DRB1*1501, has been well-established for multiple sclerosis (MS). In addition, the -168A/G CIITA promoter variant (rs3087456) has been reported to be associated with MS. Thus, a multi-stage investigation of variation within CIITA, DRB1*1501 and MS was undertaken in 6108 individuals. In stage 1, 24 SNPs within CIITA were genotyped in 1320 cases and 1363 controls (n = 2683). Rs4774 (missense +1614G/C; G500A) was associated with MS (P = 4.9 x 10(-3)), particularly in DRB1*1501 +individuals (P = 1 x 10(-4)). No association was observed for the -168A/G promoter variant. In stage 2, rs4774 was genotyped in 973 extended families; rs4774*C was also associated with increased risk for MS in DRB1*1501+ families (P = 2.3 x 10(-2)). In a third analysis, rs4774 was tested in cases and controls (stage 1) combined with one case per family (stage 2) for increased power. Rs4774*C was associated with MS (P = 1 x 10(-3)), particularly in DRB1*1501+ cases and controls (P = 1 x 10(-4)). Results obtained from logistic regression analysis showed evidence for interaction between rs4774*C and DRB1*1501 associated with risk for MS (ratio of ORs = 1.72, 95% CI 1.28-2.32, P = 3 x 10(-4)). Furthermore, rs4774*C was associated with DRB1*1501+ MS when conditioned on the presence (OR = 1.67, 95% CI = 1.19-2.37, P = 1.9 x 10(-3)) and absence (OR = 1.49, 95% CI = 1.15-1.95, P = 2.3 x 10(-3)) of CLEC16A rs6498169*G, a putative MS risk allele adjacent to CIITA. Our results provide strong evidence supporting a role for CIITA variation in MS risk, which appears to depend on the presence of DRB1*1501.

Investigating genetic interactions (epistasis) has proven difficult despite the recent advances of both laboratory methods and statistical developments. With no 'best' statistical approach available, combining several analytical methods may be optimal for detecting epistatic interactions. Using a multi-stage analysis that incorporated supervised machine learning and methods of association testing, we investigated epistatic interactions with a well-established genetic factor (PTPN22 1858T) in a complex autoimmune disease (rheumatoid arthritis (RA)). Our analysis consisted of four principal stages: Stage I (data reduction)-identifying candidate chromosomal regions in 292 affected sibling pairs, by predicting PTPN22 concordance using multipoint identity-by-descent probabilities and a supervised machine learning algorithm (Random Forests); Stage II (extension analysis)-testing detailed genetic data within candidate chromosomal regions for epistasis with PTPN22 1858T in 677 cases and 750 controls using logistic regression; Stage III (replication analysis)-confirmation of epistatic interactions in 947 cases and 1756 controls; Stage IV (combined analysis)-a pooled analysis including all 1624 RA cases and 2506 control subjects for final estimates of effect size. A total of seven replicating epistatic interactions were identified. SNP variants within CDH13, MYO3A, CEP72 and near WFDC1 showed significant evidence for interaction with PTPN22, affecting susceptibility to RA.

A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99 x 10(-16)). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53 x 10(-12)), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80 x 10(-13). Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE-associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation., Competing Interests: The authors have declared that no competing interests exist.

Aim: Type 1 diabetes (T1D) is a complex trait for which variation in the classical human leucocyte antigen (HLA) loci within the Major Histocompatibility Complex (MHC) significantly influences disease risk. To date, HLA class II DR-DQ genes confer the strongest known genetic effect in T1D. HLA loci may also influence T1D through additional inherited or non-inherited effects. Evidence for the role of increased maternal-offspring HLA compatibility, and both parent-of-origin (POO) and non-inherited maternal HLA (NIMA) effects in autoimmune disease has been previously established. The current study tested hypotheses that classical HLA loci influence T1D through these mechanisms, in addition to genetic transmission of particular risk alleles., Methods: The Type 1 Diabetes Genetics Consortium (T1DGC) cohort was of European descent and consisted of 2271 affected sib-pair families (total n = 11 023 individuals). Class I genes HLA-A, Cw and B, and class II genes HLA-DRB1, DQA1, DQB1, DPA1 and DPB1 were studied. The pedigree disequilibrium test was used to examine transmission of HLA alleles to individuals with T1D. Conditional logistic regression was used to model compatibility relationships between mother-offspring and father-offspring for all HLA loci. POO and NIMA effects were investigated by comparing frequencies of maternal and paternal transmitted and non-transmitted HLA alleles for each locus. Analyses were also stratified by gender of T1D-affected offspring., Results: Strong associations were observed for all classical HLA loci except for DPA1, as expected. Compatibility differences between mother-offspring and father-offspring were not observed for any HLA loci. Furthermore, POO and NIMA HLA effects influencing T1D were not present., Conclusions: Maternal-offspring HLA compatibility, POO and NIMA effects for eight classical HLA loci were investigated. Results suggest that these HLA-related effects are unlikely to play a major role in the development of T1D.

Genetic susceptibility to multiple sclerosis (MS) is associated with the MHC located on chromosome 6p21. This signal maps primarily to a 1-Mb region encompassing the HLA class II loci, and it segregates often with the HLA-DQB1*0602, -DQA1*0102, -DRB1*1501, -DRB5*0101 haplotype. However, the identification of the true predisposing gene or genes within the susceptibility haplotype has been handicapped by the strong linkage disequilibrium across the locus. African Americans have greater MHC haplotypic diversity and distinct patterns of linkage disequilibrium, which make this population particularly informative for fine mapping efforts. The purpose of this study was to establish the telomeric boundary of the HLA class II region affecting susceptibility to MS by assessing genetic association with the neighboring HLA-DRB5 gene as well as seven telomeric single nucleotide polymorphisms in a large, well-characterized African American dataset. Rare DRB5*null individuals were previously described in African populations. Although significant associations with both HLA-DRB1 and HLA-DRB5 loci were present, HLA-DRB1*1503 was associated with MS in the absence of HLA-DRB5, providing evidence for HLA-DRB1 as the primary susceptibility gene. Interestingly, the HLA-DRB5*null subjects appear to be at increased risk for developing secondary progressive MS. Thus, HLA-DRB5 attenuates MS severity, a finding consistent with HLA-DRB5's proposed role as a modifier in experimental autoimmune encephalomyelitis. Additionally, conditional haplotype analysis revealed a susceptibility signal at the class III AGER locus independent of DRB1. The data underscore the power of the African American MS dataset to identify disease genes by association in a region of high linkage disequilibrium.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Variation in the major histocompatibility complex on chromosome 6p21, specifically the HLA-DRB1*15 haplotype, is the strongest genetic factor for MS, yet it is estimated to account for only a portion of risk for the disease. Previous evidence has implicated the nitric oxide synthase gene (NOS2A) encoding inducible NOS on chromosome 17q11 as a potential MS susceptibility gene. To determine whether variation in the NOS2A gene contributes to MS risk, we investigated a total of 50 polymorphisms within or flanking the locus for evidence of association using a comprehensive analytical strategy. A total of 6265 members from 1858 well-characterized MS families were utilized. No evidence for overtransmission of any individual single-nucleotide polymorphism allele or haplotype to the MS-affected individuals was observed. Furthermore, different transmission rates were not observed in either DRB1*15-positive or DRB1*15-negative family subgroups, or when extreme clinical outcomes characterizing disease progression were examined. The very largest study of NOS2A variation in MS, to date, excludes even a modest role for this locus in susceptibility.

Background: Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis. We aimed to identify coexisting autoimmune phenotypes in patients with multiple sclerosis from families with several members with the disease and in their first-degree relatives., Methods: A total of 176 families (386 individuals and 1107 first-degree relatives) were characterised for a history of other autoimmune disorders. Family-based or case-control analyses were done to assess the association of cytotoxic T-lymphocyte-antigen 4 (CTLA4) and protein tyrosine phosphatase (PTPN22) variants with susceptibility to multiple sclerosis., Findings: 46 (26%) index cases reported at least one coexisting autoimmune disorder. The most common were Hashimoto thyroiditis (10%), psoriasis (6%), inflammatory bowel disease (3%), and rheumatoid arthritis (2%). 112 (64%) families with a history of multiple sclerosis reported autoimmune disorders (excluding multiple sclerosis) in one or more first-degree relatives, whereas 64 (36%) families reported no history of autoimmunity. Similar to index cases, Hashimoto thyroiditis, psoriasis, and inflammatory bowel disease were also the most common disorders occurring in family members. A common variant within CTLA4 was strongly associated with multiple sclerosis in families who had other autoimmune diseases (p=0.009) but not in families without a history of other autoimmune disorders (p=0.90)., Interpretation: The presence of various immune disorders in families with several members with multiple sclerosis suggests that the disease might arise on a background of a generalised susceptibility to autoimmunity. This distinct multiple-sclerosis phenotype, defined by its association with other autoimmune diseases, segregates with specific genotypes that could underlie the common susceptibility.

Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Objective: Multiple sclerosis (MS) is approximately twice as common among women as men. If men have greater physiologic resistance to MS, they might theoretically require stronger genetic predisposition than women to overcome this resistance. In this circumstance, men would be expected to transmit the disease more often to their children, a phenomenon known as the Carter effect. The authors evaluated whether the Carter effect is present in MS., Methods: The authors studied 441 children (45 with definite MS) of an affected father or mother (197 families of interest) from 3598 individuals in 206 multiplex pedigrees. The authors compared transmission of MS from affected men with transmission from affected women., Results: Fathers with MS transmitted the disease to their children more often (transmitted: 18, not transmitted: 99) than mothers with MS (transmitted: 27, not transmitted: 296) (p = 0.032; OR: 1.99, 95% CI: 1.05, 3.77). Adjusting for both the sex of the affected child and multiple transmissions from a single affected parent, the sex of the affected parent remained as an independent risk factor for transmission of MS to children, fathers transmitting more often than mothers (p = 0.036; OR: 2.21, 95% CI: 1.05, 4.63)., Conclusions: The authors have demonstrated the Carter effect in multiple sclerosis (MS). These observations may be explained by greater genetic loading in men that leads to relative excess paternal vs maternal transmission. Linkage analysis in genetic studies of MS may be more informative if patrilineal transmission were given additional weighting.

The major histocompatibility complex human leukocyte antigen (HLA)-DRB1*15 (DR2) haplotype is strongly associated with risk of multiple sclerosis (MS). The primary susceptibility has been localized to only approximately 200 kb encompassing the HLA-DR and -DQ loci. Further dissection of disease association with this region is demanding because of the high levels of linkage disequilibrium (LD). Recently, evidence was obtained for the involvement of a gene, potentially encoding an immune co-receptor, in another DR2-associated inflammatory condition, sarcoidosis. The implicated gene, BTNL2, is adjacent to DR and is in strong LD with HLA-DRB1. This fact, combined with a sequence relationship between BTNL2 and myelin oligodendrocyte glycoprotein, an autoantigen associated with MS, makes the gene an attractive candidate. To determine whether BTNL2 contributes to MS, we genotyped 1136 well-characterized MS families from the UK and the USA, as well as an African-American case-control data set, making this among the largest genetic studies in MS. Family-based and case-control association studies were performed for the BTNL2 and HLA-DRB1 loci. In all family data sets, the protein-truncating allele of BTNL2, implicated in sarcoidosis, was significantly over-transmitted to cases (combined data sets: global P=2.4x10(-11)). Given that the protein-truncating allele of BTNL2 virtually always occurred with DRB1*15, an effect could only be tested in DRB1*15-negative individuals or pedigrees. However, despite adequate power to detect an independent association, no difference in transmission of BTNL2 alleles or genotypes was observed in DRB1*15-negative individuals with MS. Conditional logistic regression modeling also strongly supported the conclusion that BTNL2 does not confer additional disease risk. The association of BTNL2 with MS observed in the African-American data set was also secondary to the primary DRB1*15 association.