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Praise for the First Edition "The main strength of this book is that it provides a unified framework of graphical tools for data analysis, especially for univariate and low-dimensional multivariate data. In addition, it is clearly written in plain language and the inclusion of R code is particularly useful to assist readers’ understanding of the graphical techniques discussed in the book. … It not only summarises graphical techniques, but it also serves as a practical reference for researchers and graduate students with an interest in data display." -Han Lin Shang, Journal of Applied Statistics Graphics for Statistics and Data Analysis with R, Second Edition, presents the basic principles of graphical design and applies these principles to engaging examples using the graphics and lattice packages in R. It offers a wide array of modern graphical displays for data visualization and representation. Added in the second edition are coverage of the ggplot2 graphics package, material on human visualization and color rendering in R, on screen, and in print. Features Emphasizes the fundamentals of statistical graphics and best practice guidelines for producing and choosing among graphical displays in R Presents technical details on topics such as: the estimation of quantiles, nonparametric and parametric density estimation; diagnostic plots for the simple linear regression model; polynomial regression, splines, and locally weighted polynomial regression for producing a smooth curve; Trellis graphics for multivariate data Provides downloadable R code and data for figures at www.graphicsforstatistics.com Kevin J. Keen is a Professor of Mathematics and Statistics at the University of Northern British Columbia (Prince George, Canada) and an Accredited Professional StatisticianTM by the Statistical Society of Canada and the American Statistical Association.

Objective.The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA).Methods.A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference.Results.Recommendations for the management of SpA were created. Part II: Specific Management Recommendations addresses management with nonpharmacologic methods, nonsteroidal anti-inflammatories and analgesics, disease-modifying antirheumatic drugs, antibiotics, tumor necrosis factor inhibitors, other biologic agents, and surgery. Also included are 10 modifications for application to juvenile SpA.Conclusion.These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that implementation of these recommendations will promote best practices in the treatment of SpA.

Microparticles (MPs) are small, membrane-coated vesicles released in response to injury, cell activation or apoptosis. Growing evidence suggests associations between MPs and disease manifestations in systemic sclerosis (SSc). The aim of this study is to systematically review published articles and abstracts that discuss the role of MPs in SSc. The Web of Science(®), PubMed(®) and Google Scholar databases were searched for all articles and abstracts that discussed MPs in the context of SSc. The literature search was conducted on 18 July 2013 and restricted to English-language articles and abstracts. From a total of 150 distinct articles and 10 abstracts, only 14 articles and 4 abstracts met the criteria for an attempt of quantitative synthesis. Twenty articles were accepted for a review of reviews. Conference proceedings and journals not cataloged in either Web of Science(®) or PubMed(®) or searchable by Google Scholar would have been undetected. There is a risk of valid studies with negative results going unpublished. Few studies have been conducted on MPs in patients with SSc so it was possible to thoroughly consider each. While there is low quality evidence from studies that plasma concentrations of circulating endothelial and platelet MPs are elevated in SSc patients and that plasma concentrations of circulating endothelial MPs are higher in SSc cases with either pulmonary hypertension or interstitial lung disease than those SSc cases without, definitive conclusions are not possible due to heterogeneity of the studies with respect to inclusion criteria, populations studied, laboratory analysis methods, and choice of outcome statistics.

In this paper a mixed model with nested random effects was used to model the cross-sectional area increment of lodgepole pine based on relevant explanatory variables. This model was used to show that minimum monthly temperature, monthly precipitation, and foliar biomass are positively related to the cross-sectional area increment, while an ordinal variable approximating lower trunk position and maximum monthly temperature are negatively related. It was shown that annual growth is better explained by monthly maximum and minimum temperatures than by average annual temperature and that the use of climate variables provided more reliable estimates for growth prediction than the use of the growth and density measurements from previous years. The Canadian Journal of Statistics 39: 185–189; 2011 © 2011 Statistical Society of Canada Resume: Dans cet article, un modele mixte avec des effets aleatoires emboites est utilise pour representer les accroissements transversaux de l’aire du pin de Murray a l’aide de variables explicatives pertinentes. Ce modele a permis de montrer que la temperature mensuelle minimale, la quantite de precipitation mensuelle et la biomasse foliaire sont positivement reliees a l’accroisement transversal d’aire tandis qu’une variable ordinale approximant la position de la partie inferieure du tronc et la temperature mensuelle maximale sont negativement reliees. Il est montre que la croissance annuelle est mieux expliquee par les temperatures mensuelles maximale et minimale que par la temperature annuelle moyenne et que l’utilisation des variables de climats procure des estimes plus fiables de la prediction de croissance que l’utilisation des observations sur la croissance et les mesures de densite des annees precedentes. La revue canadienne de statistique 39: 185–189; 2011 © 2011 Societe statistique du Canada

Reliability measures have been well studied over many years. Such measures have been thoroughly studied for two-factor models. Motivated by a medical research problem, point and confidence interval estimates of the intraclass correlation coefficient are extended to models containing three crossed random factors-subjects, raters, and occasions. The estimation is conducted using both analysis of variance and Monte Carlo Markov chain methods.

Objectives/Hypothesis: The article considers the interrelatedness of allergic rhinitis and chronic rhinosinusitis (CRS). The negative impact of perennial allergy and tobacco use on polyposis in sinus surgery patients is explored. Study Design: A retrospective chart review, performed by the first author over a 6-year period, of patients who underwent functional endoscopic sinus surgery for CRS. Methods: The subjects' allergy status and smoking history are scrutinized by summary statistics and a multiple linear logistic model for predicting the presence of polyps. Results: High prevalence of perennial allergic rhinitis (PAR) is seen in the subject population (56.4%). Both PAR and tobacco use are associated with nasal polyposis (P = .0073 and P = .0114, respectively). Conclusions: The close association of PAR and CRS suggests a possible causal link. Management of allergic rhinitis and tobacco cessation may provide greater control of chronic hyperplastic rhinosinusitis.

Objectives This study examines the effect of pulmonary disease on patient-reported outcomes (PROs) and patient-performed outcome (PPO) in systemic lupus erythematosus (SLE) patients at a single tertiary referral center. Methods Pulmonary function tests (PFTs), chest imaging, SLE-related damage, and disease activity were examined in 110 SLE patients. Presence was noted of abnormal PFTs, pleural disease, pulmonary hypertension (PH), pulmonary infarction, interstitial lung disease (ILD), and shrinking lung syndrome (SLS). PROs included the Medical Outcome Short Form-36 Health Survey, Pittsburgh Sleep Quality Index, Fatigue Severity Scale, Borg Dyspnea Scale, patient dyspnea and cough. The PPO of interest was the six-minute walk test (6MWT). Relationships amongst PROs, 6MWT, and pulmonary disease were studied. Results Pulmonary disease was present in 62 (56%) of 110 subjects: 54 (49%) abnormal PFT, 13 (12%) pleural disease, 12 (11%) ILD, 11 (10%) SLS and five (5%) PH. Dyspnea was the only PRO found to be significantly associated with pulmonary disease ( P = 0.0004). Participants with pulmonary disease compared to those without had significantly reduced distance ( P = 0.00015, 95% CI for mean 39–125 m) and predicted distance ( P = 0.00001, 10%–26%) on 6MWT. Conclusions Pulmonary disease is common in SLE and adversely impacts 6MWT distance and dyspnea without apparent influence on other PROs. The 6MWT may be a promising tool in the assessment of pulmonary disease in SLE.

Objective.The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA).Methods.A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. A survey was sent to the membership of the CRA to obtain an extended review that was used to finalize the recommendations.Results.Guidelines for the management of SpA were created. Part I focuses on the principles of management of SpA in Canada and includes 6 general management principles, 5 ethical considerations, target groups for treatment recommendations, 2 wait time recommendations, and recommendations for disease monitoring. Also included are 6 modifications for application to juvenile SpA.Conclusion.These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that the implementation of these recommendations will promote best practices in the treatment of SpA.

To assess the effect of injection immunotherapy on mucociliary clearance in allergic patients with the use of the saccharin test.In this prospective cohort study, mucociliary clearance in 42 allergic patients treated with injection immunotherapy was determined with the saccharin test. Of these patients, 23 were retested 1 year later to assess changes in mucociliary clearance times. Mean results for historical controls were determined in a review and meta-analysis of the existing literature.Saccharin clearance times (SCTs) were initially prolonged in allergic patients who received injection immunotherapy when compared to historical controls (one-sided P value0.05). However, after 1 year of immunotherapy, there was a significant reduction in SCTs in our patient population. This finding was independent of other evaluated patient characteristics, with the exception of nasal steroid use, which was also significantly associated with a decrease in SCT.After 1 year of injection immunotherapy, there was a significant reduction in mean SCT in our patient population. Of the other factors studied, only nasal steroid was associated with decreased mucociliary clearance times. To our knowledge, this is the first report in the literature documenting the beneficial effect of injection immunotherapy on mucociliary clearance as measured by saccharin clearance times. Nevertheless, further research is warranted, given the confounding effect of nasal steroid use.

In studies of disease inheritance, it is more convenient to collect family data by first locating an affected individual and then enquiring about the status of his or her relatives. Although the different categories of children classified by disease, sex, and other covariates may have a particular multinomial distribution among families of a given size, the numbers as ascertained do not have the same distribution because of unequal probabilities of selection of families. The introduction of weighted distributions to correct for ascertainment bias in the estimation of parameters in the classical segregation model can be traced to Fisher in 1934. This theory was presented in a general formulation by C. R. Rao at the First International Symposium on Classical and Contagious Distributions in 1963. Further expansion on the topic was given by C. R. Rao in the ISI Centenary Volume published in 1985. The effects of different two-phase sampling designs on the estimation of parameters in the classical segregation m...

It is commonly assumed that the parameter estimates of a statistical genetics model that has been adjusted for ascertainment will estimate parameters in the general population from which the ascertained subpopulation was originally drawn. We show that this is true only in certain restricted circumstances. More generally, ascertainment-adjusted parameter estimates reflect parameters in the ascertained subpopulation. In many situations, this shift in perspective is immaterial: the parameters of interest are the same in the ascertained sample and in the population from which it was drawn, and it is therefore irrelevant to which population inferences are presumed to apply. In other circumstances, however, this is not so. This has important implications, particularly for studies investigating the etiology of complex diseases.

Objectives. To outline rationale and potential strategies for rheumatology experts to be able to develop disease-specific Core Sets under the framework of the International Classification of Functioning, Disability and Health (ICF). ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact and burden on functioning of health conditions associated with impairment/disability. Methods. A combined effort of the EULAR Scleroderma Clinical Trial and Research and the ICF Research Branch was initiated to develop an ICF language for scleroderma. From our Medline literature review, using the abbreviation and spelled out version of ICF, we assembled approaches and methodological reasoning for steps of core set development. Results. The ICF can be used for patient care and policy-making, as well as the provision of resources, services and funding. The ICF is used on institutional, regional, national and global levels. Several diseases now have ICF Core Sets. Patients with complex rheumatologic diseases will benefit from a disease-specific ICF Core Set and should be included in all stages of development. ICF Core Set development for rheumatic diseases can be conducted from a number of feasible strategies. Conclusion. This overview should help to clarify useful processes leading to development of an ICF Core Set, and also provide a platform for expert groups considering such an endeavour.

Study background: Insufficient or absent angiogenesis are hallmarks of scleroderma (SSc). Microvascular change is an early manifestation of SSc followed by intimal proliferation and fibrosis of arterioles resulting in reduced blood flow and tissue ischemia. This ongoing vasculopathy in the lungs presents clinically as pulmonary hypertension and characteristically precedes lung fibrosis in patients. The purpose of this preliminary study is to elucidate possible interrelationships amongst circulating microparticles, angiogenic and angiostatic factors in SSc patients that are predictive of interstitial lung disease and high values of right ventricular systolic pressure (RVSP) by trans-thoracic Doppler-echocardiography (TTE). Methods: Nineteen cases with limited cutaneous SSc (lcSSc) and 11 cases with diffuse cutaneous SSc (dcSSc) were compared to 30 age- and sex-matched healthy controls. High resolution computed tomography was used to establish the diagnosis of interstitial lung disease and TTE was used to estimate RVSP and to diagnose putative pulmonary arterial hypertension (PAH). Plasma concentrations of circulating factors were assessed in patients and controls. Results: Angiopoetin-2, endostatin, E-selectin and platelet microparticles were higher in lcSSc cases compared to healthy controls (p

To determine the potential effects of angiopoietins Ang-1 and Ang-2 and their receptor Tie-2 in patients with systemic sclerosis (SSc). Twenty-six patients with limited SSc (l-SSc) and fourteen patients with diffuse SSc (d-SSc) were evaluated and compared to age-matched controls. Plasma levels of soluble sAng-1, sAng-2, sTie-2, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and endostatin were measured. Associations between these factors and clinical parameters were assessed. Levels of circulating factors and the ratios sAng-2/sAng-1 and sAng-2/sTie-2 were not different between l-SSc and d-SSc cases but were collectively higher compared to their controls: sAng-1 (p = 0.0108); sAng-2 (p

In this paper we present a new object-oriented cohesion metric at the runtime boundary, based on number of runtime variable accesses. Only a small amount of previous work so far has been done with runtime boundary metrics [1, 2, 3, 4, 6]. This area has considerable potential: it promises more accurate quality measurements that have been available before, since quality is measured on the actual running code. We first propose the metric, then we compute the metric on an open source software package and validate it by comparing it to static cohesion metrics and expert cohesion data. Our results indicate that the metric does measure cohesion, and thus is worthy of future studies to determine its full utility.

Summary Beginning with Galton, Various authors have proposed non-iterative estimators of the correlation coefficient that measure the degree of similarity among siblings. However, these extimators lose efficiency appreciable for certain ranges of values of the correlation coefficient. An estimator formed by an algebraic combination of two non-iterative extimators based on Smith (1957) is shown by simulation to be nearly full efficent for teh full range of values of the coefficent. A new estimator given by the best linear combination of these extimators offers a practical improvement for large values of the coefficent. The discussion conceludes with an example.

SUMMARY In genetics, the term interclass correlation has been used to refer to the parent-offspring and son-daughter correlations within families. Under the assumption of variable family sizes and normality, we derive the asymptotic variance of the maximum likelihood estimator of the sondaughter interclass correlation.

In this paper several papers that have been written on mobile agents and robots are surveyed with a view toward determining the state of the art of software mobile agents running on robotic platforms.

Background A recent consensus project (Saketkoo et al, Thorax 2014) recommended a minimum core set of outcome measures for use in future clinical trials of CTD-ILD and IPF. The World Health Organization (WHO) introduced the International Classification of Functioning, Disability, and Health (ICF) as a scientific method of disability data collection and a universal framework of >1200 categories describing disability in terms of the bio-psycho-social model with consideration of environmental and personal factors. For accurate representation of disease, ease of healthcare provision and fair allocation of resources, it is essential that ICF Core Sets be established for rare and complex diseases. Methods Per updated ICF linkage rules, each instrument from the published CTD-ILD and IPF core sets were deconstructed to meaningful concepts and independently linked by 2 health professionals experienced in ICF linkage (RE, LAS). Inter-linker agreement on independent linkages was analyzed (KK). A 3rd linker (OD) arbitrated if irreconcilable linkages occurred. Results Eighty-two ICF categories were identified under the 4 ICF domains for 6 patient questionnaires and 3 traditional objective measures. The proportion of agreement ranged from 0.79 (95% CI: 0.62, 0.91) to 0.93 (0.76, 0.99) (Table 1) with the overall proportion of inter-linker agreement 0.86 (0.82, 0.89). 20 new “Personal Factors” and 7 suggested modifications were generated to capture important disease-specific qualities not elsewhere described in ICF, e.g. “pf_embarrassed by cough”; “pf_panic/afraid when can9t get breath”; pf_fear of hurting self by overexertion; d4508_walking pace or b469_bouts of coughing to describe paroxysmal coughing spells that are often disabling in this condition. Conclusions This is the first effort to map CTD-ILD and IPF outcome measures to the ICF. ICF Core Sets provide stream-lined disease-specific coding of disability data that support global, regional and personal health-related parity across cultures, age and socioeconomic status; enabling fair assessment of disability for policy-making, service provision, funding and rural/urban infrastructural modifications. Validation steps are planned for item analysis and potential development of a single composite instrument for clinical trials and clinical practice. The availability of ICF Core Sets in CTD-ILD and IPF will afford clinicians a smoother transition to ICD-11 which is under development and will meld diagnostic coding with the ICF. Disclosure of Interest L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee, R. Escorpizo: None declared, K. Keen: None declared, K. Fligelstone: None declared, S. Birring: None declared, M. Lammi: None declared, J. Lasky: None declared, D. LeSage: None declared, E. Renzoni: None declared, A. M. Russell: None declared, C. Sarver: None declared, M. B. Scholand: None declared, J. Varga: None declared, O. Distler: None declared

Objectives The purpose of this study was to provide further evidence that allergic rhinitis is an important factor in chronic and recurrent acute rhinosinusitis. Specifically, this study shows that perennial allergens play a more significant role than seasonal allergens. Study design and setting Census by chart review of patients with chronic and recurrent acute rhinosinusitis presenting to the Department of Otolaryngology at the MetroHealth Medical Center, Cleveland, OH. Methods All participants had allergy testing done either by RAST or intradermal skin endpoint titration utilizing a battery of seasonal and perennial antigens. Results Of the 48 voluntary participants analyzed in this study, 57.4% had a positive allergy test. Most patients in the study were sensitive to more than one allergen. Of the patients with a positive allergy test, 92% demonstrated sensitivity to one or more perennial allergens—most prominently, molds and dust mites. Conclusions Perennial allergy has a statistically significant association with chronic and recurrent acute rhinosinusitis. Significance The diagnosis and management of perennial allergies may be beneficial when treating chronic sinus disease.

Twelve teams of investigators constituted a group which analyzed phenotypes related to metabolic syndrome, making use of the available longitudinal measurements from the family component of the Framingham Heart Study or the simulated data, as distributed by Genetic Analysis Workshop 13 (GAW13). Body mass index, obesity, lipid abnormalities, glucose, or combinations of these traits were analyzed by this group. A wide variety of approaches were taken to construct phenotypes from the longitudinal measurements, including considering single or multiple cross-sectional time points, single ages, minimum values, maximum values, means, other lifetime values, ever/never dichotomy, or age at onset of some threshold value. Approaches also differed in the family structures utilized (sib pairs to full extended pedigrees), the genetic data considered (two-point or multipoint), and the statistics calculated (model-free and parametric), and led to a diverse set of analyses being performed. Inferences were made about heritability, and attempts were made to map underlying genes. Over 40 genome-wide linkage analyses were conducted. Despite the broad range of approaches, several regions of the genome were repeatedly identified across multiple analyses.

Methods to unravel the genetic determinants of non-Mendelian diseases lie at the next frontier of statistical approaches for human genetics. It is generally agreed that, before proceeding with segregation or linkage analysis, the trait under study ought to be shown to exhibit familial correlation. By coding dichotomous traits as binary variables, a single robust approach in the estimation of pedigree correlations, rather than two distinct approaches, can be used to assess the potential heritability of a trait, and, latterly, to examine the mode of inheritance. The asymptotic theory to conduct hypothesis tests and confidence intervals for correlations among different members of nuclear families is well established but is applicable only if the nuclear families are independent. As a further contribution to the literature, we derive the asymptotic sampling distribution of correlations between random variables among arbitrary pairs of members in extended families for the Pearson product-moment estimator with generalized weights. This derivation is done without assuming normality of the traits. The sampling distribution is shown to be asymptotically normal to first order, and hence large-sample hypothesis tests and confidence intervals with estimates of the variances and correlation coefficients are proposed. Discussion concludes with an example and a suggestion for future research.

Purpose To explore whether patterns of sexual relationships, such as sequential (nonoverlapping in time) or concurrent (overlapping in time), are more important indicators of sexually transmitted disease (STD) risk among adolescents than number of sexual partners. Methods Data from 4707 sexually active adolescents from the National Longitudinal Study of Adolescent Health were analyzed based on reported heterosexual relationships during the past 18 months. Adolescents were categorized as engaging in single, sequential, or concurrent sexual relationships. Demographic, behavioral, and social characteristics of each group were compared and multivariate logistic models were fit to determine STD risk associated with sexual relationship patterns and overall number of sexual partners during this same time period. Results Thirty-five percent of sexually active teens had more than one partner in the past 18 months, and 40% of these multiple partnerships were overlapping or concurrent in time. Teens in sequential and concurrent relationships reported lower condom use and a higher degree of regret of having sex owing to alcohol use than those in single relationships. Teens in concurrent relationships also reported the lowest self-efficacy to use contraceptives. Teens in sequential or concurrent relationships were more likely to report an STD than single-relationship teens (odds ratio 2.3 and 3.9, respectively); however, they were not statistically different from each other. Number of sexual partners during this same time period was not associated with STD risk once relationship pattern was considered. Conclusion Adolescents who engage in sequential or concurrent sexual relationships differ in some important demographic, behavioral, and social characteristics and, when compared with those who engage in single relationships, have a significantly greater risk for STDs over and above the number of sexual partners.

Background SSc affects multiple organ systems resulting in an unlimited combination of types and degrees of disability in patients. Skin fibrosis, ischemic pain, ulceration, arthritis, contractures of small and large joints, and myopathy as well as cardiopulmonary, renal and gastrointestinal effects carry significant burden on emotional, social and physical functioning. ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact caused by health conditions on functioning and disability. The ICF uses a standardized alphanumerical language to describe health states in terms of the bio-psycho-social model. The ICF is accepted by national and international health care and policy-making systems to assess the impact of disease on personal, scientific, economic and service levels. Methods A comprehensive literature search in PubMed was performed with the following keywords: outcome measures, SSc, health, rehabilitation, function, quality of life, mental, sexual, pain and disease activity to identify 5 validated measures representing the broadest range of SSc manifestations (OD, LAS). Meaningful concepts were identified in the instruments and linked to the ICF by two health professionals familiar with ICF linking rules (RE, LAS). Their agreement was analyzed (KK). Results Nine new codes were created to address the absence of ICF codes to describe the SSc disease experience as contained within the instruments. ICF codes were linked to 5 validated SSc instruments:5 ICF codes to the Hand Mobility in Scleroderma Test, 5 the Modified Rodnan Skin Score, 9 to the Raynaud’s Condition Score, 40 to the Scleroderma Health Assessment Questionnaire, and 25 to the SSc Gastrointestinal Tract Instrument. These 5 instruments identified 71 distinct categories for the folllowing domains: 26 for Body Function, 6 for Body Structure, 33 for Activity and Participation and 6 for External Factors. The proportion of agreement ranged from 0.8611 (95% CI: 0.7500, 0.9444) for HAMIS to 0.9647 (0.9175, 1.000) for mRSS, when corrected for chance ranged from 0.7097 (0.5291, 0.8835) to 0.8964 (0.7631, 1.0000). Overall, the proportion of agreement was 0.9359 (0.9172, 0.9506), which when adjusted for chance was 0.7230 (0.6453, 0.7797). By either measure, the degree of agreement between the linkers, a physiotherapist and a rheumatologist, was high. Conclusions This first step, in a methodological series to establish an ICF language for SSc, was successful in both high agreement of linking and in exploring the potential challenges of linking a complex multi-organ system disease. Further face, content and construct validation strategies are now underway. Of the diseases already linked to ICF, SSc is the most complex thus requiring precise strategies to gain knowledge from SSc experts– including patients, rehabilitation and nurse experts. A composite of all validated SSc outcome measures is soon to be available for ICF engaged health systems. Thus, the global, regional and personal impact of SSc across cultures, age and socioeconomic status may be assessed fairly for use in policy making and provision of services and funding. Disclosure of Interest L. A. Saketkoo Grant/Research support from: Actelion, United Therapeutics, R. Escorpizo: None Declared, K. Keen Speakers Bureau: Merck, K. Fligelstone: None Declared, O. Distler Consultant for: Actelion, BMS, Fibrogen, Egonex, Pfizer, Sonofi Aventis, Genetech, Active Biotech, Novartis, UCB, 4D Science

Background Systemic sclerosis (SSc) is an inflammatory obliterative microvasculopathy disorder of unknown etiology characterized by fibrosis predominantly in the dermis but also in internal organs. The selectin family of adhesion molecules is responsible for the early stages of extravasation through leukocyte adhesion and recruitment involving initial rolling of leukocytes on the endothelium. L-selectin appears to play a critical role in comparison to P- and E-selectin with L-selectin deficient mice essentially equivalent to normal mice treated with antibodies blocking P- and E-selectin. Furthermore, L-selectin may exert its effect at inflammatory sites by mediating leukocyte-leukocyte interactions that facilitate the recruitment of neutrophils and lymphocytes. Uniquely, L-selectin, shed after cellular activation, retains functional activity in its soluble form and is involved in the regulation of leukocyte attachment to an inflamed endothelium [1]. L-selectin ligands are induced on the endothelium of inflammatory sites and the cutaneous sites of chronic inflammation. Levels of (soluble) sL-selectin have been reported as elevated with concomitant decreased expression on CD8+ cells in SSc suggesting that L-selectin is a possible target for therapeutic modulation of skin damage in diffuse cutaneous disease [2]. Objectives The purpose of this study is to determine in limited SSc or diffuse SSc whether sL-selectin concentration in plasma is a marker of skin involvement using the modified Rodnan skin score (mRSS) as a parameter of the extent of skin disease. Methods Nineteen cases with limited SSc and 11 cases with diffuse SSc were evaluated and compared to age- and sex-matched controls. Criteria of the American College of Rheumatology were used to establish the diagnosis of SSc. Skin involvement was assessed using the modified Rodnan skin score. Plasma concentrations of sL-selectin were assessed in patients and controls. Results The distribution of sL-selectin concentration in plasma appears to be normal, by the Shapiro-Wilk test, for controls (p=0.1329), limited SSc (p=0.4153) and diffuse SSc (p=0.3657). A paired t test for the mean difference in sL-selectin concentration for limited SSc cases compared to their matched controls is statistically insignificant (p=0.2424, 95% CI: -62, 229 ng/ml) while the mean difference for diffuse SSc cases compared to their matched controls is statistically significant (p=0.0369, 95% CI: -362, -14 ng/ml). The mean sL-selectin concentrations for limited SSc and diffuse SSc are significantly different by Welch’s two-sample t test (p=0.0005, 95% CI: 7, 20 ng/ml). The distribution of mRSS seems to be normal, by the Shapiro-Wilk test, for limited SSc (p=0.3300) and diffuse SSc (p=0.2318). Assuming normality, we find no association between mRSS and plasma sL-selectin concentration in limited SSc (p=0.9944) but a statistically significant negative correlation in diffuse SSc (R 2 =73.11%, p=0.0008). The interpretation of the slope for diffuse SSc cases is that for each increase of 100 ng/ml in soluble L-selectin concentration in plasma, the modified Rodnan skin score drops 4.22 (95% CI: 2.29, 6.16). Conclusions Modulation of circulating L-selectin is a promising target for reducing skin damage in diffuse SSc patients. References Schleiffenbaum B, Spertini O, Tedder TF. J Cell Biol 1992;199:229-38. Shimada Y, Hasegawa K, Takehara K, et al. Clin Exp Immunol 2001;124:474-9. Disclosure of Interest J. Dunne Grant/Research support from: Actelion Pharmaceuticals, Scleroderma Association of British Columbia, S. van Eeden Grant/Research support from: The Heart and Stroke Foundation of Canada, GlaxoSmithKline Inc., and the Canadian Institutes for Health Research, K. Keen Grant/Research support from: Scleroderma Association of British Columbia, Speakers Bureau: Merck Canada Inc.

Background Elevated blood pressure in middle age is a major risk factor for subsequent cardiovascular complications. An important longitudinal characteristic of blood pressure is the "tracking phenomenon". Tracking is defined as the persistence of the rank of a person's blood pressure level in a group over a long period of time. In this analysis, we used the Framingham data to investigate whether there are some genes responsible for this phenomenon. Results Both two-point and multipoint linkage analyses were applied to family members with complete data only and to all family data with missing values imputed by a Gaussian model. The results of two-point linkage analysis indicated that two loci for linkage with the intercept were on chromosomes 10 and 13, and two loci for linkage with both slope and intercept were on chromosomes 1 and 3. Multipoint linkage analysis indicated only one region, 200–240 cM on chromosome 1, to be linked with both intercept and slope. For the intercept of SBP, the highest LOD (4.43) was found at 214 cM when missing data were imputed, and the highest LOD (2.81) was at 231 cM for the complete case data. For the slope of SBP, the highest multipoint LODs were 3.63 at 227 cM and 2.02 at 234 cM for the complete case data and imputation data, respectively. Conclusion One or more genes in the range of 200–240 cM on chromosome 1 may be related to the tracking phenomenon of SBP.

SUMMARY Because the maximum likelihood estimator for the intraclass correlation p does not exist in closed form for the unbalanced one-way random-effects model, several noniterative estimators have been proposed for p in normal populations. Estimators that exclude all families of only one member have been recommended in the literature of familial correlations; however, these estimators lose efficiency appreciably for certain ranges of values of p. Indeed, no single estimator can have the highest efficiency along the full range of the intraclass correlation coefficient. Three proposed estimators, each formed by combining a pair of noniterative estimators of which one constituent estimator excludes families having only one member, are shown by simulation to be nearly fully efficient for the full range of values of p. A mathematical expression is given that can be used to calculate the large-sample standard errors of all known noniterative estimators of the intraclass correlation.

SUMMARY A noniterative method for estimating the interclass correlation coefficient is derived from the technique of weighted sums of squares. The asymptotic variance of this estimator is derived under the assumption of normality. Through extensive Monte Carlo simulations, the sample variance of this estimator is found not to differ greatly from that of the maximum likelihood estimator. An important problem in genetics is the estimation of the degree of resemblance between a mother and her children as measured by the interclass correlation coefficient. Because parents produce differing numbers of offspring during their reproductive period, the maximum likelihood estimation of the interclass correlation presents computational difficulties requiring an iterative solution. Therefore, a number of noniterative estimators have been proposed in the literature. These estimators will be shown to be associated with special cases of the generalized estimator derived from the weighted sums of squares of measurements on parents and offspring. Because our purpose is to provide a comprehensive approach to the noniterative point and interval estimation problems for the interclass correlation coefficient, the asymptotic variance of the proposed estimator is derived under the assumption of normality. Moreover, the sample variances of two special cases of the proposed estimator are compared to that of the maximum likelihood estimator through Monte Carlo simulations. By a theoretical argument, it is shown that the estimator proposed by Srivastava (1984) has a uniformly smaller asymptotic variance than the ensemble estimator proposed by Rosner, Donner & Hennekens (1977). Smith (1957) used the weighted sums-of-squares approach for the estimation problem concerning the intraclass correlation coefficient which measures the degree to which siblings resemble one another. Our results together with those of Smith (1957) provide a unified approach to estimation problems concerning familial correlations among a parent and offspring.