The study design and rationale of the randomized controlled trial: translating COPD guidelines into primary care practice

Background: Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disease associated with significant clinical burden and is estimated to affect 15 million individuals in the US. Although a large number of individuals are diagnosed with COPD, many individuals still remain undiagnosed due to the slow progression of the disorder and lack of recognition of early symptoms. Not only is there under-diagnosis but there is also evidence of sub-optimal evidence-based treatment of those who have COPD. Despite the development of international COPD guidelines, many primary care physicians who care for the majority of patients with COPD are not translating this evidence into effective clinical practice. Method/Design This paper describes the design and rationale for a randomized, cluster design trial (RCT) aimed at translating the COPD evidence-based guidelines into clinical care in primary care practices. During Phase 1, a needs assessment evaluated barriers and facilitators to implementation of COPD guidelines into clinical practice through focus groups of primary care patients and providers. Using formative evaluation and feedback from focus groups, three tools were developed. These include a computerized patient activation tool (an interactive iPad with wireless data transfer to the spirometer); a web-based COPD guideline tool to be used by primary care providers as a decision support tool; and a COPD patient education toolkit to be used by the practice team. During phase II, an RCT will be performed with one year of intervention within 30 primary care practices. The effectiveness of the materials developed in Phase I are being tested in Phase II regarding physician performance of COPD guideline implementation and the improvement in the clinically relevant outcomes (appropriate diagnosis and management of COPD) compared to usual care. We will also examine the use of a patient activation tool - ‘MyLungAge’ - to prompt patients at risk for or who have COPD to request spirometry confirmation and to request support for smoking cessation if a smoker. Discussion Using a multi-modal intervention of patient activation and a technology-supported health care provider team, we are testing the effectiveness of this intervention in activating patients and improving physician performance around COPD guideline implementation. Trial registration ClinicalTrials.gov, NCT0123756

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

Patient-facing Technology for Identification of COPD in Primary Care

The proliferation of mobile devices and emergence of interoperable ‘mHealth’ apps is accelerating development and deployment of patient-facing risk assessments in primary care. The present study describes a user-centered design and an agile development approach to creation of an app for assessing lungfunction as part of a randomized controlled trial for the   dentification of chronic obstructive lung disease in primary care. Seventeen patients recruited from a hospital-based, ambulatory family medicine clinic agreed to be videotaped while using the app, Lung Age, on a first-generation iPad prior to their providerencounter. Subsequently, participants were interviewed using a semi-structured interview guide upon exiting their medical visit. Observational data indicated that participants took advantage of the portability and flexibility of the tablet device in the exam room to engage with the Lung Age app with the optionto share and discuss their results with their providers. Results from the semistructured interviews indicated that participants perceived the Lung Age app as intuitive and easy to use. These results demonstrate that tablet computers and mHealth apps can be used to deploy acceptable and useable electronic risk assessments in primary care settings. Future research focused on the impact and outcomes of patient-centered, mHealth apps for risk screening in primary care is warranted

Automated Internet-based pain coping skills training to manage osteoarthritis pain

Osteoarthritis (OA) is a leading cause of disability in the United States and globally, [14; 39] and the burdens it causes are expected to increase as the world’s population ages [14; 23]. Non-pharmacological treatments are a recommended component of current guidelines for treating OA pain [53]. Although evidence is mixed that people benefit from non-pharmacological treatments such self-management interventions and patient education [e.g., 17; 25; 38; 45], one non-pharmacological therapy—pain coping skills training (PCST)—has demonstrated more consistently positive outcomes [38]. PCST focuses specifically on educating people about cognitive and behavioral pain coping skills and helping them master those skills so they can become more actively involved in managing their pain--the most common and debilitating OA symptom [33]. It includes two main components: 1) a rationale linking pain to patterns of cognitive, emotional, and behavioral pain responses, and 2) training in skills such as attention diversion (e.g., relaxation), cognitive restructuring (to address catastrophizing and other maladaptive cognitive patterns), and activity patterns (e.g., activity-rest cycling). It has traditionally been delivered in-person by a trained therapist over 10-12 weeks. Randomized controlled trials demonstrate that PCST significantly improves pain and other outcomes [e.g., 24; 29; 30; 31; 63]. Moreover, interventions such as PCST have fewer adverse effects than pharmacological pain treatments and are well-received by patients. Thus, research supports the efficacy of in-person PCST. However, access to this intervention is limited by barriers such as lack of trained therapists, the substantial resources needed to deliver it, and the need for people to travel to in-person training held at scheduled times [22; 59] There is a clear need for an approach that makes PCST more accessible. The Internet—a proven method for delivering behavioral interventions—provides an avenue for meeting this need [15; 42; 58; 65], especially given older adults’ increasing use of the Internet [69]. The present pilot study was a two-arm randomized controlled trial conducted to evaluate the potential efficacy and acceptability of an eight-week, automated, Internet-based version of PCST called PainCOACH. This program was designed to retain key therapeutic features of the in-person PCST protocol, simulating in-person PCST while presenting training in an easy-to-use format with guided instruction, individualized feedback, interactive exercises, and animated demonstrations [57]. We hypothesized that: (1) PainCOACH would reduce pain (primary outcome) and improve pain-related interference with functioning, pain-related anxiety, self-efficacy for pain management, and positive and negative affect; and (2) acceptability would be high. Our overarching goal was to use findings from this early-stage research to refine the program and study protocol in preparation for a larger-scale trial. Additionally, we explored sex differences in responses to PainCOACH, based on evidence in our own lab and others showing significant sex differences in pain, pain responses, pain behavior, and pain coping in people with OA [e.g., 1; 19; 27; 32; see 54; 62; 67]. The potential for men and women to respond differently to pain interventions is important but rarely evaluated in research

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection