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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.

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 integrate...

BackgroundThe 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.ObjectiveFor 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.DesignCross-sectional multilevel observational study of 16 randomly selected practices in two large accountable care organizations (ACOs).ParticipantsPatients 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 measuresPatient-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 resultsHaving 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.ConclusionsDiabetic 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.

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.

Background Multi-stakeholder alliances – groups of payers, purchasers, providers, and consumers that work together to address local health goals – are frequently used to improve health care quality within communities. Under the Aligning Forces for Quality (AF4Q) initiative, multi-stakeholder alliances were given funding and technical assistance to encourage the use of health information technology (HIT) to improve quality. We investigated whether HIT adoption was greater in AF4Q communities than in other communities. Methods Drawing upon survey data from 782 small and medium-sized physician practices collected as part of the National Study of Physician Organizations during July 2007 – March 2009 and January 2012—November 2013, we used weighted fixed effects models to detect relative changes in four measures representing three domains: use of electronic health records (EHRs), receipt of electronic information from hospitals, and patients’ online access to their medical records. Results Improvement on a composite EHR adoption measure was 7.6 percentage points greater in AF4Q communities than in non-AF4Q communities, and the increase in the probability of adopting all five EHR capabilities was 23.9 percentage points greater in AF4Q communities. There was no significant difference in improvement in receipt of electronic information from hospitals or patients’ online access to medical records between AF4Q and non-AF4Q communities. Conclusion By linking HIT to quality improvement efforts, AF4Q alliances may have facilitated greater adoption of EHRs in small and medium-sized physician practices, but not receipt of electronic information from hospitals or patients’ online access to medical records. Implications Multi-stakeholder alliances charged with promoting HIT to advance quality improvement may accelerate adoption of EHRs.

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.

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.

Physician practices have been growing in size, and becoming more commonly owned by hospitals, over time. We use survey data on physician practices surveyed at two points in time, linked to Medicare claims data, to investigate whether changes in practice size or ownership are associated with changes in the use of care management, health information technology (HIT), or quality improvement processes. We find that practice growth and becoming hospital-owned are associated with adoption of more quality improvement processes, but not with care management or HIT. We then investigate whether growth or becoming hospital-owned are associated with changes in Medicare spending, 30-day readmission rates, or ambulatory care sensitive admission rates. We find little evidence for associations with practice size and ownership, but the use of care management practices is associated with lower rates of ambulatory care sensitive admissions.

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.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.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.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.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.

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.

ObjectivesTo 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 settingPublicly 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 designWe 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 methodsWe linked physician participation data from Medicare's Physician Compare to the NSPO3 survey.Principal findingsThere 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&nbsp

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.Trend analyses of 3 large national surveys of physician practices.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.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.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.

PurposeImplementation 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.MethodsWe 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.ResultsOverall, 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

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.

Background: Prior studies suggest structurally integrating healthcare organizations may not yield care that is integrated for patients. This research has been limited by lack of comprehensive measures of integrated patient care. Our study establishes an evidence base of care integration from the patient’s perspective among a national sample in the United States using a reliable and valid survey. We explore the relationship between patient-perceived integration and elements of organizational integration among medical groups.Methods: We refined and administered the Patient Perceptions of Integrated Care (PPIC) survey. It was theoretically derived, refined through pilot-testing, cognitive testing, and advisory panel input, and tested for reliability and validity. Psychometric analysis supported six dimensions of patient-perceived integration: (1) Provider Knowledge of the Patient, (2) Staff Knowledge about the Patient’s Medical History, (3) Specialist Knowledge about the Patient’s Medical History, (4) Support for Self-directed Care, (5) Support for Medication and Home Health Management, and (6) Test Result Communication. We also created an index of Integration following Hospitalization. This structure achieved good model fit and internal, discriminant, and construct validity. We administered the survey across a stratified random sample of 12,364 Medicare beneficiaries with at least two chronic conditions who had received care from a sample of 150 medical groups from the National Study of Physician Organizations (NSPO3). The final sample included 3,067 Medicare beneficiaries (26% response after 412 exclusions). We extracted data on the medical groups from the NSPO3 for five dichotomized dimensions: large/small size, physician/hospital ownership, primary care/multi-specialty, an information technology sophistication index related to electronic medical record and e-prescribing use (high/low), and an index regarding key care management process intensity (high/low). We conducted analyses using ordered logistic regression models with robust standard errors and weighting by response probability, adjusting for patient demographic, health and psychological characteristics.Results: Among the seven dimensions of integration, Test Result Communication exhibited the most consistently positive responses; each of its three items had over 70% of respondents reporting the most favorable option. Support for Self-directed Care and Support for Medication and Home Health Management exhibited consistently the least favorable responses. For Support for Self-directed Care, none of its five items had more than half of responses in the most favorable option, and four of the five items had over 20% of responses in the least favorable option. For Support for Medication and Home Health Management, only one of its four items revealed a majority in the most favorable option (at 55%).We did not find evidence of strong, consistent relationships between medical group characteristics and integrated care from the patient's perspective. Being a patient in a multispecialty group was associated with higher patient-perceived integration in all domains except for test result communication, but only the relationship with staff knowledge was statistically significant (odds ratio = 1.70; p

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.

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.

Purpose – The purpose of this paper is to identify opportunities for improving primary care services for people with chronic illnesses by comparing how Sweden and US services use evidence-based practices (EBPs), including digital health technologies (DHTs). Design/methodology/approach – A national primary healthcare center (PHCC) heads surveys in 2012-2013 carried out in both countries in 2006. Findings – There are large variations between the two countries. The largest, regarding effective DHT use in primary care centers, were that few Swedish primary healthcare compared to US heads reported having reminders or prompts at the point of care (38 percent Sweden vs 84 percent USA), despite Sweden’s established electronic medical records (EMR). Swedish heads also reported 30 percent fewer centers receiving laboratory results (67 percent Sweden vs 97 percent USA). Regarding following other EBPs, 70 percent of Swedish center heads reported their physicians had easy access to diabetic patient lists compared to 14 percent in the USA. Most Swedish PHCC heads (96 percent) said they offered same day appointment compared to 36 percent in equivalent US practices. Practical implications – There are opportunities for improvement based on significant differences in effective practices between the countries, which demonstrates to primary care leaders that their peers elsewhere potentially provide better care for people with chronic illnesses. Some improvements are under primary care center control and can be made quickly. There is evidence that people with chronic illnesses in these two countries are suffering unnecessarily owing to primary care staff failing to provide proven EBP, which would better meet patient needs. Public finance has been invested in DHT, which are not being used to their full potential. Originality/value – The study shows the gaps between current and potential proven effective EBPs for services to patients with chronic conditions. Findings suggest possible explanations for differences and practical improvements by comparing the two countries. Many enhancements are low cost and the proportionate reduction in suffering and costs they bring is high.

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.

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.

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 The accountable care organization (ACO) is a new organizational form to manage patients across the continuum of care. There are numerous ques- tions 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 com- pared 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 pri- mary 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 experi- ence, 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 productiv- ity, 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 qual- ity, 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 bet- ter patient experience, improved population health, and lower per capita costs.

There are now more than seven hundred accountable care organizations (ACOs) in the United States. This article describes some of their most salient characteristics including the number and types of contracts involved, organizational structures, the scope of services offered, care management capabilities, and the development of a three-category taxonomy that can be used to target technical assistance efforts and to examine performance. The current evidence on the performance of ACOs is reviewed. Since California has the largest number of ACOs (N=67) and a history of providing care under risk-bearing contracts, some additional assessments of quality and patient experience are made between California ACOs and non-ACO provider organizations. Six key issues likely to affect future ACO growth and development are discussed, and some potential “diagnostic” indicators for assessing the likelihood of potential antitrust violations are presented.

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.

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.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.Systematic identification of patients who use tobacco increased in large (26% to 91%, p0.0001) and small-medium practices (69% to 83%, p0.0001). 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%, p0.0001) for small-medium practices. State-mandated coverage was associated with the use of cessation processes in small-medium practices (p0.0001), as was pay for performance participation (p0.0001); public reporting (p0.0001); Medicaid revenue (p=0.02); and practice size (p0.0001). Among large practices, predictors were practice size (p0.0001); hospital ownership (p=0.004); public reporting (p=0.03); and primary care practice (p=0.04).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.

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 Affordable Care Act (ACA) is expected to extend health insurance coverage for up to 25.3 million Americans by 2022 (Holahan et al. 2012). A major policy question is whether the expanded coverage and the associated increased demand for care will be affordable over time. This depends importantly on the ability of delivery systems to provide more efficient and effective care. One important component of the ACA was the creation of Accountable Care Organizations (ACOs). ACOs are entities willing to be held accountable for the costs and quality of care for a defined population of patients. When the ACA became law, such would-be organizations were likened by some observers to unicorns—they exist in our imagination, but no one has actually seen one (Morrison 2011; PWC 2011). But as the ACA has evolved, a number of new value-based payment and delivery system reforms have been established through the ACO initiative, including the Medicare Shared Savings and Pioneer ACO programs (Berwick 2011). Private payers are also actively fostering the development of ACOs (Larson et al. 2012). There are currently 30 Pioneer ACOs, 337 shared savings arrangements (Evans 2013), and 239 private payer risk-bearing contracts for a total of 606 ACOs (Muhlestein 2014). ACOs are now present in most health care markets and 55 percent of Americans live in areas where ACOs exist (Lewis et al. 2013). While there is an emerging knowledge base on some of the successes and challenges faced by early ACOs (Fisher et al. 2012; Larson et al. 2012; Lewis et al. 2012; Song et al. 2012; McWilliams, Landon, and Chernew 2013), no information has been published to date on the extent to which individual physician practices have joined or are planning to join an ACO. This includes existing practices in which most physicians are employed but in which the practice has not yet entered into risk-bearing contracts; a defining criterion of an ACO. Such information is critical to assessing the likely uptake and spread of ACOs across the country. Will they spread fast enough to make a difference? Will a sufficient number exist to make value-based purchasing viable nationally (Ryan and Damberg 2013)? Data are also lacking on the capabilities that practices may need to contain cost growth, make improvements in clinical quality and patient experience, and improve overall population health—the much touted “triple aim.” This study addresses the level of physician practice participation and planned participation in ACOs along with the factors associated with each. We examined data from 1,183 practices responding to the National Survey of Physician Organizations III, conducted in 2012 and 2013. We identified practices that are currently part of an ACO, others that were planning to join within a year, and still others that were not involved and had no plans to become involved. We compared these groups on a variety of background characteristics and, importantly, on their adoption of care processes thought to assist with the management of patients with chronic illness such as asthma, congestive heart failure, depression, and diabetes, which account for the majority of health care expenditures in the United States (Anderson and Horvath 2004). Specifically, we examined the extent to which practices that were a part of an ACO differed from those who were in the planning stage or had no involvement at all with regard to such factors as size, ownership, governance, specialty mix, location, and their ability to manage patients with complex chronic illness. Understanding differences in these practice characteristics can help to assess the future growth of physician practice involvement in ACOs and whether the impact of ACOs may be different for early adopting physician practices compared to later adopters (Westphal, Gulati, and Shortell 1997).

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 extended major histocompatibility complex (xMHC) is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs) in childhood BCP-ALL cases (n=567) enrolled in the Northern California Childhood Leukemia Study (NCCLS) compared with population controls (n=892). Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036), located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046). Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation. © 2013 Urayama et al.

Integrating care for patients with multiple chronic conditions is essential to improving quality. Yet little is known about care integration from the patient’s perspective and how it relates to med...

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. Major histocompatibility complex (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 SNPs 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.

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.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoantibodies to nuclear and cell surface antigens. Although the etiology of SLE remains unknown, evidence for genetic susceptibility is well established. The HLA class II alleles DRB1*1501, *0301, and *0801 and the HLA class I alleles A*01 and B*08 in the major histocompatibility complex (MHC) region are consistently associated with SLE. HLA loci may also influence SLE through additional inherited or noninherited mechanisms. Differences in maternal and paternal transmission rates, or parent-of-origin effects, have not been previously examined in SLE. One potential mechanism influencing disease susceptibility is “genomic imprinting” due to epigenetic modification of the genome. This modification results in unequal transcription of parental alleles and subsequent allele expression, depending on whether alleles were transmitted from the mother or from the father. Increased HLA compatibility between a mother and her offspring is hypothesized to contribute to the risk of autoimmune disease. Maternal–offspring effects can present as excess HLA compatibility between the mother and affected offspring (Figure 1). In mice, HLA similarity between mother and fetus has been shown to promote the persistence of maternal cells in the offspring (maternal microchimerism) following pregnancy (1). Figure 1 Maternal–offspring HLA compatibility relationships. The developing immune system of the fetus is also directly exposed to noninherited maternal antigens (NIMAs) in utero (2). Exposure to NIMAs can have a lifelong influence on the immune system and has been theorized to tolerize or predispose to autoimmune reactions. A tolerogenic effect may explain the longer survival of renal transplants from sibling donors expressing NIMAs versus noninherited paternal HLA. Decreased B cell responses to HLA class I NIMAs in humans have been reported (3). Recent data suggest that fetuses may also develop T cell tolerance to NIMAs in utero through tolerogenic fetal regulatory T cells that are maintained throughout life (4). The aim of this study was to test the hypothesis that the DRB1 locus influences SLE through these novel biologic mechanisms in addition to genetic transmission of particular HLA risk alleles.

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 = 9.99×10−16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10−12), *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 = 2.80×10−13. 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., Author Summary Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and involvement of multiple organ systems. Although the cause of SLE remains unknown, several lines of evidence underscore the importance of genetic factors. As is true for most autoimmune diseases, a substantial genetic contribution to disease risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6. This region of the genome contains a large number of genes that participate in the immune response. However, the full contribution of this genomic region to SLE risk has not yet been defined. In the current study we characterize a large number of SLE patients and family members for approximately 2,000 MHC region variants to identify the specific genes that influence disease risk. Our results, for the first time, implicate four different MHC regions in 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.

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.

Summary 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.

Background: Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism. Methods: Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. Results: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of e2 or e4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96–1.34 and OR 0.89, 95% CI 0.78–1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative ( p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. Conclusion: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

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

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.