Randomized prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test.

PURPOSE: To evaluate the diagnostic yield and clinical relevance of clinical genome sequencing (cGS) as a first genetic test for patients with suspected monogenic disorders. METHODS: We conducted a prospective randomized study with pediatric and adult patients recruited from genetics clinics at Massachusetts General Hospital who were undergoing planned genetic testing. Participants were randomized into two groups: standard-of-care genetic testing (SOC) only or SOC and cGS. RESULTS: Two hundred four participants were enrolled, 202 were randomized to one of the intervention arms, and 99 received cGS. In total, cGS returned 16 molecular diagnoses that fully or partially explained the indication for testing in 16 individuals (16.2% of the cohort, 95% confidence interval [CI] 8.9-23.4%), which was not significantly different from SOC (18.2%, 95% CI 10.6-25.8%, P = 0.71). An additional eight molecular diagnoses reported by cGS had uncertain relevance to the participant's phenotype. Nevertheless, referring providers considered 20/24 total cGS molecular diagnoses (83%) to be explanatory for clinical features or worthy of additional workup. CONCLUSION: cGS is technically suitable as a first genetic test. In our cohort, diagnostic yield was not significantly different from SOC. Further studies addressing other variant types and implementation challenges are needed to support feasibility and utility of broad-scale cGS adoption.

A model of movement dysfunction provides a classification system guiding diagnosis and therapeutic care in spinal pain and related musculoskeletal syndromes: a paradigm shift-Part 1.

An integrative functional model largely based upon clinical observation and analysis of the more common features of neuromusculoskeletal-dysfunction encountered in clinical practice is presented as a working hypothesis in Part 1. This endeavours to incorporate contemporary knowledge and practice. The enlightened work of Professor Vladimir Janda has undoubtedly been seminal in the development of this model; however a further evolution of his work is elaborated on in this paper. Thinkers from the human potential movement as well as the scientific community have provided further valuable insights to assist our understanding of function. A related simple classification system of two main clinical subgroups with back pain and related disorders is offered in Part 2. These are based upon the most usual dysfunctional postural and movement strategies. Further distillation provides a number of dysfunction syndromes which will have predictable consequences. This is not a mathematical, computer generated or theoretical biomechanical model. This model describes 'what it is' that we see in our patients, and endeavours to be an overview of the movement related causes of back pain. It provides a clinically useful and practical framework to assist the practitioner in diagnosis and to better understand the development and perpetuation of most spinal pain and related disorders. In so doing, more rational, functional and effective manual and exercise therapy interventions can ensue.

A model of movement dysfunction provides a classification system guiding diagnosis and therapeutic care in spinal pain and related musculoskeletal syndromes: a paradigm shift-Part 2.

An integrative functional model largely based upon the observation and analysis of the more common features of neuromusculoskeletal dysfunction encountered in clinical practice was presented as a working hypothesis in Part 1. The functional inter relationships between these regional and general features and their contribution to the development and perpetuation of local and or referred spinal pain syndromes was explored. Here we look more closely at clinical patterns of presentation. A simple classification system of clinical subgroups with back pain and related disorders is offered. These more commonly observed dysfunctional postural and movement strategies have been distilled into a number of dysfunction syndromes which will have predictable consequences. In beginning to provide a map of the tendencies towards, or actual, changed postural and movement responses seen in people with spinal pain and related disorders, this model provides a valuable reference for those working in the body work and movement therapies realm. It is a practical and useful clinical tool to assist diagnosis and help better understand the development and perpetuation of most spinal pain and related disorders. In so doing, more rational, functional and effective therapeutic and research interventions can ensue.

Understanding practice patterns and low-density lipoprotein cholesterol goal attainment implications of switching patients from simvastatin in a health plan setting.

OBJECTIVE: To understand the practice patterns and National Cholesterol Education Panel (NCEP) Adult Treatment Panel (ATP) III low-density lipoprotein cholesterol (LDL-C) goal attainment rates after switching patients from simvastatin (SMV) to other statins or the combination of SMV and ezetimibe (EZE). METHODS: This retrospective study linked claims and laboratory data from a national health plan. Patients were included if they were taking SMV and were switched to other statins or a fixed-dose combination of SMV and EZE between July 1, 2005, and June 30, 2006. Patients taking dual SMV/EZE before switch were excluded from the study. The NCEP ATP III risk status of patients at switch was assessed based on medical claims, pharmacy claims, and laboratory values in the 12-month preswitch period. Lipid data (available on a patient subset) were used to estimate patients' goal attainment status at and after switch. RESULTS: Of 134 168 patients taking SMV, 11 929 (8.9%) switched to other statins or SMV/EZE. The mean age of switching patients was 54 years (standard deviation, 9 years), 61% were men, 50% were high risk, and 30% were moderate risk. The mean time to switch among new starters of SMV (n = 3379) was 77 days. Forty percent (n = 4772) of the total switches occurred among those taking the lower doses (5, 10, and 20 mg) of SMV. Most patients switched from SMV to SMV/EZE (60.5%), followed by atorvastatin (17.3%), rosuvastatin (10.1%), lovastatin (8.6%), pravastatin (2.9%), and fluvastatin (0.7%). Similarly, most patients switching from higher doses of SMV switched to SMV/EZE (52.5%), followed by atorrestatin (21.1%) and rosuvastatin (10.1%). Overall, 55.6% (758 of 1362) of patients were at ATP III goal at the time of switch from SMV (across all doses; n = 758), and 56.1% (292 of 521) of those taking lower doses were at goal at time of switch. A majority (69.9%) of patients who were at goal and switched from SMV (across all doses) were switched to SMV/EZE, and 61.6% of those at lower doses of SMV switched to the combination drug. Of patients who were not at goal at switch (n = 604), 73.3% attained ATP III LDL-C goal after switch. The mean percent LDL-C reduction that was needed to attain LDL-C goal at switch from SMV (n = 604) was 18.1%. CONCLUSIONS: There is an opportunity to further increase LDL-C goal attainment rates among patients switched from SMV. The clinical, prescription benefit design, and economic implications of the finding that a majority of patients are at goal when switched from SMV and a majority of patients are being switched from SMV to SMV/EZE need to be further examined.