Publications by authors named "Richard J Cook"

197 Publications

Depression and Anxiety Reduce the Probability of Achieving a State of Sustained Minimal Disease Activity in Patients with Psoriatic Arthritis.

Arthritis Care Res (Hoboken) 2021 Mar 4. Epub 2021 Mar 4.

Psoriatic Disease Program, Centre for Prognosis Studies in the Rheumatic Diseases, Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Canada.

Objective: We aimed to determine whether the presence of depression or anxiety is associated with the achieving sustained minimal disease activity (MDA) in patients with psoriatic arthritis (PsA).

Methods: Adult patients satisfying CASPAR criteria prospectively followed from 2008 to 2017 were included. A standard protocol including physician assessment and patient-reported outcomes defined whether patients achieved sustained MDA, defined when MDA criteria were met for two or more consecutive visits. The presence of depression/anxiety was determined using three definitions: 1) a score of <=38 on the Mental Component Summary score of the SF-36 questionnaire; 2) a score of <=56 on the Mental Health sub-scale score; and 3) rheumatologist's report of a diagnosis or treatment for depression/anxiety. A discrete time-to-event analyses was conducted based on a proportional odds model to identify factors associated with achieving sustained MDA.

Results: 743 patients were included in the study. The number of patients identified as having depression/anxiety at baseline was: Definition 1- 331 (44.54%), 2- 364 (48.99%), and 3- 211 (28.4%). 337 patients (45.36%) failed to achieve sustained MDA. The presence of depression/anxiety was associated with reduced probability of achieving sustained MDA with OR=0.30, p <0.0001, OR=0.34, p <0.0001, and OR=0.47, p <0.0001 for Definitions 1, 2 and 3, respectively. Other variables associated with a reduced probability of achieving sustained MDA included the Charlson comorbidity index and fibromyalgia.

Conclusion: Symptoms of anxiety/depression reduce the probability of achieving sustained MDA in PsA. Comprehensive management of PsA should include measures for addressing these comorbidities.
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http://dx.doi.org/10.1002/acr.24593DOI Listing
March 2021

Gene-based analysis of bi-variate survival traits via functional regressions with applications to eye diseases.

Genet Epidemiol 2021 Mar 1. Epub 2021 Mar 1.

Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, District of Columbia, USA.

Genetic studies of two related survival outcomes of a pleiotropic gene are commonly encountered but statistical models to analyze them are rarely developed. To analyze sequencing data, we propose mixed effect Cox proportional hazard models by functional regressions to perform gene-based joint association analysis of two survival traits motivated by our ongoing real studies. These models extend fixed effect Cox models of univariate survival traits by incorporating variations and correlation of multivariate survival traits into the models. The associations between genetic variants and two survival traits are tested by likelihood ratio test statistics. Extensive simulation studies suggest that type I error rates are well controlled and power performances are stable. The proposed models are applied to analyze bivariate survival traits of left and right eyes in the age-related macular degeneration progression.
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http://dx.doi.org/10.1002/gepi.22381DOI Listing
March 2021

Comparative Efficacy of Different Triage Methods for Psoriatic Arthritis - Prospective Study in a Rapid Access Clinic.

Arthritis Care Res (Hoboken) 2021 Feb 5. Epub 2021 Feb 5.

Division of Rheumatology, Women's College Hospital and the Department of Medicine, University of Toronto, Toronto, ON, Canada.

Objectives: The study aimed to identify the optimal combination of triage methods to identify PsA among psoriasis patients with musculoskeletal symptoms in a rapid access clinic and to describe their outcome after 1 year.

Methods: Patients with psoriasis and no prior diagnosis of PsA were referred for assessment of their musculoskeletal complaints. Each patient was assessed by the following three triage modalities: 1) assessment by an advanced practice physiotherapist; 2) targeted musculoskeletal ultrasound (MSK-US) and; 3) PsA screening questionnaires. The patients were then evaluated by a rheumatologist who determined their disease status and classified them as: "Not PsA", "Possibly PsA" or "PsA". Patients returned for a one year follow up visit and were re-assessed for change in their disease status. Sensitivity and specificity were calculated for each individual modality as well as for combinations of modalities.

Results: 203 patients with psoriasis and musculoskeletal symptoms were enrolled. 8.8% were classified as PsA and 23.6% as possibly PsA. There was no significant difference in the individual performance of the modalities. The highest sensitivity was seen with MSK-US (89%) and the highest specificity was found with the Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire (79%). The addition of MSK-US data improved the performance of the modalities. A total of 9 patients converted to PsA after 1 year. All patient reported outcome measures have significantly improved at one year (P<0.001).

Conclusion: Combining MSK-US with a screening questionnaire for PsA improved the triage of patients with suspected PsA.
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http://dx.doi.org/10.1002/acr.24570DOI Listing
February 2021

Malignancy in psoriatic disease: Results from prospective longitudinal cohorts.

Semin Arthritis Rheum 2021 Feb 24;51(1):144-149. Epub 2020 Dec 24.

Center for Prognostic Studies in the Rheumatic Diseases, Krembil Research Institute, University Health Network, Toronto, ON Canada; Department of Medicine, University of Toronto, Toronto, ON Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada. Electronic address:

Objectives: To estimate the prevalence and incidence of malignancy and its types in psoriatic arthritis (PsA) and psoriasis without arthritis (PsC) patients, in comparison to the general population, and to identify the predictive factors for developing cancer in psoriatic disease (PsD).

Methods: PsA patients followed prospectively since 1978 and PsC patients followed since 2006 at 6-to-12 month intervals according to a standard protocol were included. Malignancies were recorded prospectively and linkages with Cancer Care Ontario and the Death Registry were carried out to confirm the presence and type of malignancy up to December 2016. Standardized incidence ratios (SIR) were calculated for overall cancers and by age and sex. Cox regression analysis was conducted to identify risk factors associated with the development of malignancy after the diagnosis of PsD.

Results: 2051 patients (PsD) were included of whom 228 (11%) developed cancer. 168 patients developed cancer after first clinic visit and are included in this report. Overall SIR for malignancy was 0.83 (0.68, 1.00), SIR for females was 1.06 (0.80, 1.37), and for males was 0.67 (0.50, 0.88). The most common malignancies were skin, breast, and hematological. Skin cancer was the only specific cancer that had a higher incidence than the general population with SIR = 3.37 (1.84, 5.66). There was insufficient evidence to suggest an increased risk of malignancy associated with biologics use.

Conclusions: In this long-term prospective follow-up of patients with PsA and PsC the overall malignancy risk was not found to be higher than the general population, while skin cancer increased.
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http://dx.doi.org/10.1016/j.semarthrit.2020.12.008DOI Listing
February 2021

Selection models for efficient two-phase design of family studies.

Stat Med 2021 Jan 17;40(2):254-270. Epub 2020 Oct 17.

Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Ontario, Canada.

Family studies routinely employ biased sampling schemes in which individuals are randomly chosen from a disease registry and genetic and phenotypic data are obtained from their consenting relatives. We view this as a two-phase study and propose the use of an efficient selection model for the recruitment of families to form a phase II sample subject to budgetary constraints. Simple random sampling, balanced sampling and use of an approximately optimal selection model are considered where the latter is chosen to minimize the variance of parameters of interest. We consider the setting where family members provide current status data with respect to the disease and use copula models to address within-family dependence. The efficiency gains from the use of an optimal selection model over simple random sampling and balanced sampling schemes are investigated as is the robustness of optimal sampling to model misspecification. An application to a family study on psoriatic arthritis is given for illustration.
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http://dx.doi.org/10.1002/sim.8772DOI Listing
January 2021

Analysis of time-to-event for observational studies: Guidance to the use of intensity models.

Stat Med 2021 Jan 11;40(1):185-211. Epub 2020 Oct 11.

Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, New York, USA.

This paper provides guidance for researchers with some mathematical background on the conduct of time-to-event analysis in observational studies based on intensity (hazard) models. Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing time-dependent covariates. We discuss prediction based on hazard models and difficulties when attempting to draw proper causal conclusions from such models. Finally, we present a series of examples where the methods and check lists are exemplified. Computational details and implementation using the freely available R software are documented in Supplementary Material. The paper was prepared as part of the STRATOS initiative.
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http://dx.doi.org/10.1002/sim.8757DOI Listing
January 2021

Determining the long-term health burden and risk of sequelae for 14 foodborne infections in British Columbia, Canada: protocol for a retrospective population-based cohort study.

BMJ Open 2020 08 31;10(8):e036560. Epub 2020 Aug 31.

British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.

Introduction: Over one in eight Canadians is affected by a foodborne infection annually; however, the long-term consequences, including the risks and costs of sequelae, are unclear. We aim to estimate the health burden and direct costs of 14 infections commonly transmitted by food, considering the acute illness and subsequent sequelae and mortality, for the population of British Columbia, Canada (~4.7 million).

Methods And Analysis: We will conduct a population-based retrospective cohort study of the British Columbia provincial population, over a 10-year study period (1 January 2005 to 31 December 2014). Exposure is defined as a provincially reported illness caused by , , , hepatitis A virus, , non-typhoidal spp, Typhi, Paratyphi, Shiga toxin-producing , , or (excluding ). We will link individual-level longitudinal data from eight province-wide administrative health and reportable disease databases that include physician visits, hospitalisations and day surgeries, deaths, stillbirths, prescription medications (except those to treat HIV) and reportable foodborne diseases. Using these linked databases, we will investigate the likelihood of various sequelae and death. Hazard models will be used to estimate the risk of outcomes and their association with the type of foodborne infection. Epidemiological analyses will be conducted to determine the progression of illness and the fraction of sequelae attributable to specific foodborne infections. Economic analyses will assess the consequent direct healthcare costs.

Ethics And Dissemination: This study has been approved by a University of Waterloo Research Ethics Committee (no 30645), the University of British Columbia Behavioral Research Ethics Board (no H16-00021) and McGill University's Institutional Review Board (no A03-M12-19A). Results will be disseminated via presentations to academics, public health practitioners and knowledge users, and publication in peer-reviewed journals. Where such publications are not open access, manuscripts will also be available via the University of Waterloo's Institutional Repository (https://uwspace.uwaterloo.ca).
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http://dx.doi.org/10.1136/bmjopen-2019-036560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462161PMC
August 2020

Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial.

Lancet Haematol 2020 Sep;7(9):e640-e648

Michael G DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada; McMaster Centre for Transfusion Research, Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.

Background: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin.

Methods: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 10 cells per L before major surgery or less than 50 × 10 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 10 cells per L before major surgery or 45 × 10 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov, NCT01621204.

Findings: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49-55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; p=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI -2·1%; p=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred.

Interpretation: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles.

Funding: GlaxoSmithKline and Novartis.
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http://dx.doi.org/10.1016/S2352-3026(20)30227-1DOI Listing
September 2020

The impact of an alcohol policy change on developmental trajectories of youth alcohol use: examination of a natural experiment in Canada.

Can J Public Health 2021 Apr 6;112(2):210-218. Epub 2020 Aug 6.

University of Waterloo, 200 University Ave West, Waterloo, ON, N2L 3G1, Canada.

Objectives: In 2015, the Liquor Control Board of Ontario (LCBO) authorized sale of alcohol in some Ontario grocery stores. This research evaluates the impact of the new policy on alcohol use patterns of youth in a quasi-experimental setting with two control groups.

Methods: The sample consists of 2267 grade 9 students attending 60 secondary schools across Ontario (n = 56) and Alberta (n = 4), who provided 4-year linked longitudinal data (2013-2014 to 2016-2017) in the COMPASS study. The study used the frequency of drinking and the frequency of binge drinking to characterize alcohol use behaviours.

Results: Latent transition analysis found four statuses of alcohol use: abstainer, periodic drinker, low-risk drinker, and high-risk regular drinker. The new policy had no negative impact among periodic and low-risk drinkers, but the risk of transitioning from the abstainer (lowest risk status) to high-risk regular drinker (highest risk status) among the exposed cohort was 1.71 times greater post-policy than pre-policy change, compared with those of Ontario-unexposed (0.50) and Alberta-unexposed cohorts (1.00). The probability of sustaining high-risk drinking among the exposed cohort increased by a factor of 1.76, compared with 1.13-fold and 0.89-fold among the Ontario-unexposed and Alberta-unexposed cohorts, respectively.

Conclusion: Youth are more likely to transition from abstinence to high-risk regular drinking, and high-risk regular drinkers are more likely to maintain their behaviours in the jurisdictions exposed to the latest change in LCBO policy authorizing grocery stores to sell alcohol. When formulating policy interventions, youth access to alcohol should be considered in order to reduce their harmful alcohol consumption.
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http://dx.doi.org/10.17269/s41997-020-00366-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910382PMC
April 2021

Limitations of the particle immunofiltration assay test for diagnosis of heparin-induced thrombocytopenia.

Am J Hematol 2020 09 1;95(9):E250-E254. Epub 2020 Jul 1.

Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.

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http://dx.doi.org/10.1002/ajh.25901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496181PMC
September 2020

Mortality in psoriatic arthritis: Risk, causes of death, predictors for death.

Semin Arthritis Rheum 2020 08 23;50(4):571-575. Epub 2020 May 23.

Centre for Prognostic Studies in the Rheumatic Diseases, Toronto Western Hospital, University of Toronto, Toronto, ON Canada; Institute of Medical Science, University of Toronto, Toronto, ON Canada. Electronic address:

Background/objectives: Mortality studies in psoriatic arthritis (PsA) have provided inconsistent results. This study aimed to: 1) Estimate trends in mortality rates among PsA patients over calendar time; 2) Evaluate cause-specific mortality rates in patients with PsA compared to the general population; 3) Identify predictors for mortality in PsA.

Methods: The study was carried out at the University of Toronto Psoriatic Arthritis Clinic where patients are followed prospectively according to a standard protocol at 6- to 12- month intervals. Standardized mortality ratios (SMRs) were calculated overall, by age, and by sex with reference to the Ontario population. Causes of death were recorded by ICD9 and ICD10 codes and cause-specific SMRs were computed. Cox regression models were used to identify predictors for mortality among PsA patients.

Results: Among 1490 patients followed over 15062.8 patient-years, 225 (15%) confirmed deaths were recorded (111 females, 114 males). The overall SMR was 0.92 (95% CI: 0.81-1.05), the sex-specific SMRs were 1.08 (95% CI: 0.89-1.30) for females and 0.81 (95% CI: 0.66-0.97) for males. The age-specific SMRs were 3.36 (95% CI: 1.61-6.18), 0.97 (95% CI: 0.68-1.34), 0.88 (95% CI: 0.73-1.06) and 0.86 (95% CI: 0.66-1.11) for 20-39, 40-59, 60-79 and above 80 years of age, respectively. Major causes of death included malignant neoplasms (n=61; SMR=0.97, 95% CI: 0.72-1.28), acute myocardial infarction (n=32; SMR=1.11, 95% CI: 0.74-1.58), and pneumonia (n=14; SMR=2.46, 95% CI: 1.27-4.31). Factors found to be associated with increased mortality include elevated acute phase reactants, presence of comorbidities such as heart disease and cancer, and lower education level.

Conclusion: Young patients with PsA are at increased mortality risk. Better control of comorbidities may reduce this risk.
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http://dx.doi.org/10.1016/j.semarthrit.2020.04.001DOI Listing
August 2020

Assessing the accuracy of predictive models with interval-censored data.

Biostatistics 2020 Mar 13. Epub 2020 Mar 13.

Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, ON N2L 3G1, Canada.

We develop methods for assessing the predictive accuracy of a given event time model when the validation sample is comprised of case $K$ interval-censored data. An imputation-based, an inverse probability weighted (IPW), and an augmented inverse probability weighted (AIPW) estimator are developed and evaluated for the mean prediction error and the area under the receiver operating characteristic curve when the goal is to predict event status at a landmark time. The weights used for the IPW and AIPW estimators are obtained by fitting a multistate model which jointly considers the event process, the recurrent assessment process, and loss to follow-up. We empirically investigate the performance of the proposed methods and illustrate their application in the context of a motivating rheumatology study in which human leukocyte antigen markers are used to predict disease progression status in patients with psoriatic arthritis.
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http://dx.doi.org/10.1093/biostatistics/kxaa011DOI Listing
March 2020

Remission in psoriatic arthritis: Definition and predictors.

Semin Arthritis Rheum 2020 12 3;50(6):1494-1499. Epub 2020 Feb 3.

Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Psoriatic Arthritis Program, University Health Network, Centre for Prognosis Studies in The Rheumatic Diseases, Toronto Western hospital, Toronto, Ontario, Canada. Electronic address:

Objective: To determine the frequency of remission defined by the absence of the various disease manifestations of psoriatic arthritis (PsA) and identify predictors for remission.

Methods: Patients followed at the PsA clinic between 2000 and 2015 were included. Patients are assessed at 6- to 12-month intervals according to a standard protocol. Remission was defined as a visit that patients had no tender or swollen joints, no inflammatory back pain, no tender entheseal sites, minimal skin involvement with BSA<1%, patient pain on visual analog scale (VAS) score of <15, patient global disease activity VAS score of <20, Health Assessment Questionnaire (HAQ) score <0.5. We used imputation approach to determine remission status for visits with incomplete criteria for each patient.

Results: Data from 985 patients (57% males, average age of 47.4 years) were included in this study. From 2000 to 2015, 175 (18%) patients achieved remission at least once and 92 (9%) experienced sustained remission over at least 2 consecutive visits. In a multivariate Weibull regression analysis for the time to remission, higher BMI was associated with lower chance of remission (HR = 0.96, p = 0.012), while the use of biologics increased the chance of achieving remission (HR = 1.48, p = 0.034). The effect of biologics was also significant on the chance of achieving sustained remission for 2 or more consecutive visits (HR = 1.76, p = 0.020). However, biologics were not significantly associated with sustained remission when it was defined based on 3 or more consecutive visits.

Conclusion: Remission occurred at least once in 18% of the patients with PsA while sustained remission occurred in 9% of the study sample. Having higher BMI would reduce the achievement of remission. The use of biologic agents increased not only the chance of remission, but also the chance of sustained remission for at least 12 months.
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http://dx.doi.org/10.1016/j.semarthrit.2020.01.012DOI Listing
December 2020

Mitigating bias from intermittent measurement of time-dependent covariates in failure time analysis.

Stat Med 2020 Mar 3. Epub 2020 Mar 3.

Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Ontario.

Cox regression models are routinely fitted to examine the association between time-dependent markers and a failure time when analyzing data from clinical registries. Typically, the marker values are measured periodically at clinic visits with the recorded value carried forward until the next assessment. We examine the asymptotic behavior of estimators from Cox regression models under this observation and data handling scheme when the true relationship is based on a Cox model using the current value of the marker. Specifically, we explore the impact of the marker process dynamics, the clinic visit intensity, and the marginal failure rate on the limiting value of the estimator of the marker effect from the Cox model. We also illustrate how a joint multistate model that accommodates intermittent observation of the time-varying marker can be formulated. Simulation studies demonstrate that the finite sample performance of the naive estimator aligns with the asymptotic results and shows good performance of the estimators from the joint model. We apply both methods to data from a study of bone markers and their effect on the development of skeletal complications in metastatic cancer.
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http://dx.doi.org/10.1002/sim.8517DOI Listing
March 2020

The association between synovial fluid serine proteinase activity and response to intra-articular corticosteroid injection in psoriatic arthritis.

Clin Rheumatol 2020 Aug 25;39(8):2355-2361. Epub 2020 Feb 25.

Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Krembil Research Institute, University Health Network, University of Toronto, 399 Bathurst Street 1E-416, Toronto, Ontario, M5T 2S8, Canada.

Introduction/objectives: Intra-articular corticosteroid (IAS) injections are often used for the immediate relief of pain and inflammation in the joint of psoriatic arthritis (PsA) patients. However, studies identifying factors that predict response to the IAS injections are lacking. We aimed to assess the usefulness of serine proteinase activity measurements in PsA synovial fluid (SF) samples obtained at the time of injection in predicting clinical response.

Methods: The PsA patients with available SF samples from the knee joint were identified from the University of Toronto PsA cohort. Clinical response was defined as an absence of tenderness or swelling in the injected joint at the first post-injection visit, at either 3 or 6 months. SF proteinase activity was determined by measuring cleavage of fluorogenic tri-peptide substrates for trypsin-like (VPR-AMC and VLK-AMC) and chymotrypsin-like (AAPF-AMC) serine proteinases. Generalized estimating equation (GEE) models were used to investigate factors associated with response.

Results: A total of 32 patients with 60 injected joints and data available for follow-up at 3 or 6 months were included in the analysis, with 25 (41.7%) injected joints resulting in clinical response. Age, sex, active joint count, systemic medications and SF serine proteinase activity at the time of injection were included as covariates. Only treatment with biologics was significantly associated with response at 3 or 6 months in the multivariate reduced model (OR 3.02, p = 0.027).

Conclusions: We could not demonstrate an association between SF serine proteinase activity and response to IAS injection. Biologic agents significantly improve the likelihood of achieving clinical response.
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http://dx.doi.org/10.1007/s10067-020-05003-9DOI Listing
August 2020

Multistate analysis from cross-sectional and auxiliary samples.

Stat Med 2020 02 10;39(4):387-408. Epub 2019 Dec 10.

Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, ON, Canada.

Epidemiological studies routinely involve cross-sectional sampling of a population comprised of individuals progressing through life history processes. We consider features of a cross-sectional sample in terms of the intensity functions of a progressive multistate disease process under stationarity assumptions. The limiting values of estimators for regression coefficients in naive logistic regression models are studied, and simulations confirm the key asymptotic results that are relevant in finite samples. We also consider the need for and the use of data from auxiliary samples, which enable one to fit the full multistate life history process. We conclude with an application to data from a national cross-sectional sample assessing marker effects on psoriatic arthritis among individuals with psoriasis.
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http://dx.doi.org/10.1002/sim.8411DOI Listing
February 2020

The illness-death model for family studies.

Biostatistics 2019 Nov 19. Epub 2019 Nov 19.

Department of Statistics and Actuarial Science, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada.

Family studies involve the selection of affected individuals from a disease registry who provide right-truncated ages of disease onset. Coarsened disease histories are then obtained from consenting family members, either through examining medical records, retrospective reporting, or clinical examination. Methods for dealing with such biased sampling schemes are available for continuous, binary, and failure time responses, but methods for more complex life history processes are less developed. We consider a simple joint model for clustered illness-death processes which we formulate to study covariate effects on the marginal intensity for disease onset and to study the within-family dependence in disease onset times. We construct likelihoods and composite likelihoods for family data obtained from biased sampling schemes. In settings where the disease is rare and data are insufficient to fit the model of interest, we show how auxiliary data can augment the composite likelihood to facilitate estimation. We apply the proposed methods to analyze data from a family study of psoriatic arthritis carried out at the University of Toronto Psoriatic Arthritis Registry.
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http://dx.doi.org/10.1093/biostatistics/kxz048DOI Listing
November 2019

Independence conditions and the analysis of life history studies with intermittent observation.

Biostatistics 2019 Nov 11. Epub 2019 Nov 11.

Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, ON N2L 3G1, Canada.

Multistate models provide a powerful framework for the analysis of life history processes when the goal is to characterize transition intensities, transition probabilities, state occupancy probabilities, and covariate effects thereon. Data on such processes are often only available at random visit times occurring over a finite period. We formulate a joint multistate model for the life history process, the recurrent visit process, and a random loss to follow-up time at which the visit process terminates. This joint model is helpful when discussing the independence conditions necessary to justify the use of standard likelihoods involving the life history model alone and provides a basis for analyses that accommodate dependence. We consider settings with disease-driven visits and routinely scheduled visits and develop likelihoods that accommodate partial information on the types of visits. Simulation studies suggest that suitably constructed joint models can yield consistent estimates of parameters of interest even under dependent visit processes, providing the models are correctly specified; identifiability and estimability issues are also discussed. An application is given to a cohort of individuals attending a rheumatology clinic where interest lies in progression of joint damage.
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http://dx.doi.org/10.1093/biostatistics/kxz047DOI Listing
November 2019

Identifying patterns of alcohol use among secondary school students in Canada: A multilevel latent class analysis.

Addict Behav 2020 01 5;100:106120. Epub 2019 Sep 5.

School of Public Health and Health Systems, University of Waterloo, Canada. Electronic address:

Introduction: Harm from alcohol use depend not only on the volume of consumption but also on drinking patterns. This study identifies patterns of alcohol consumption in youth and investigates how these patterns vary across schools and whether individual- and school-level factors are associated with engagement in patterns of alcohol consumption.

Methods: The sample consists of 45,298 grade 9 to 12 students attending 89 secondary schools across Ontario and Alberta (Canada), who participated in the COMPASS study during the school year 2013-14. The frequency of drinking, the frequency of binge drinking, and age of alcohol-use initiation were used to characterize alcohol use patterns.

Results: The multilevel latent class analysis identified 4 student-level latent groups and 2 school-level latent groups. Student-level groups of youth were characterized as non-drinkers (44.2%), light drinkers (41.8%), regular drinkers (11.1%), and heavy drinkers (2.9%). Two groups of schools were characterized as either low-use (44.9%) or high-use (55.1%) schools, with significantly different probability of membership in each student-level group. Male students (OR 1.30) and upper grades (OR 1.93) were significantly associated with membership in higher use groups of individuals. The median household income and the number of off-premise alcohol outlets had no significant association with patterns of alcohol consumption within schools.

Conclusions: A large proportion of students reported a level of drinking, suggesting that, in addition to delaying the onset of alcohol use, interventions need to encourage drinker students to quit drinking or lower their consumption. Schools may need to select and/or alter external interventions according to the dominant patterns of alcohol use among their students.
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http://dx.doi.org/10.1016/j.addbeh.2019.106120DOI Listing
January 2020

Liver Abnormalities in Patients with Psoriatic Arthritis.

J Rheumatol 2020 06 15;47(6):847-853. Epub 2019 Oct 15.

From the Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network, Toronto; Department of Statistics and Actuarial Science, University of Waterloo, Waterloo; University of Toronto, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Rheumatic Disease Unit, Department of Internal Medicine, Phramongkutlao Hospital and College of Medicine, Bangkok, Thailand.

Objective: We aimed to determine the prevalence and incidence, and to identify the factors associated with liver abnormalities in patients with psoriatic arthritis (PsA).

Methods: From a longitudinal cohort study, we identified PsA patients with either elevated serum transaminase or alkaline phosphatase levels or liver disease after the first visit to the PsA clinic (cases). Controls were subjects from the same cohort who never had such abnormalities or liver disease. Cases and controls were matched 1:1 by sex, age at the first clinic visit, and followup duration; variables at the onset of the first appearance of liver test abnormality associated with liver abnormalities were identified using univariate logistic and multivariate logistic regression analyses.

Results: Among 1061 patients followed in the PsA clinic, 343 had liver abnormalities. Two hundred fifty-six patients who developed liver abnormalities after the first visit were identified as cases, and 718 patients were identified as controls. The prevalence of liver abnormalities was 32% and the incidence was 39/1000 patient-years where there were 256 cases over 6533 total person-years in the PsA cohort. Liver abnormalities were detected after a mean (SD) followup duration of 8.3 ± 7.8 years. The common causes of liver abnormalities were drug-induced hepatitis and fatty liver. Independent factors associated with liver abnormalities were higher body mass index (BMI), daily alcohol intake, higher damaged joint count, elevated C-reactive protein, and use of methotrexate, leflunomide, or tumor necrosis factor inhibitors.

Conclusion: Liver abnormalities are common among patients with PsA and are associated with higher BMI, more severe disease, and certain therapies.
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http://dx.doi.org/10.3899/jrheum.181312DOI Listing
June 2020

Identifying trajectories of alcohol use in a sample of secondary school students in Ontario and Alberta: longitudinal evidence from the COMPASS study.

Health Promot Chronic Dis Prev Can 2019 Sep;39(8-9):244-253

School of Public Health and Health Systems, University of Waterloo, Waterloo, Ontario, Canada.

Introduction: Despite evidence indicating a rapid progression in use of alcohol during adolescence, little is known about the ways patterns of drinking develop over time. This study investigated patterns of alcohol use within a cohort of youth in Ontario and Alberta and the probability of changes between patterns.

Methods: The sample consists of two-year linked longitudinal data (school year 2013/14 to 2014/15) from 19 492 students in Grades 9 to 12 in 89 secondary schools across Ontario and Alberta, Canada, who participated in the COMPASS study. The latent class analysis used two self-reported items about the frequency of drinking (measured as none, monthly, weekly, or daily use) and the frequency of binge drinking (measured as none, less than or once a month, 2-4 times a month, or more than once week) to characterize patterns of alcohol use. The effects of gender, ethnicity and cannabis and cigarette use on alcohol use patterns were examined.

Results: The study identified four drinking patterns: non-drinker, periodic drinker (reported monthly drinking and no binge drinking), low-risk drinker (reported monthly drinking and limited binge drinking) and high-risk regular drinker (reported drinking 1-3 times a week and binge drinking 2-4 times a month). Non-drinker was the most prevalent pattern at baseline (55.1%) and follow-up (39.1%). Periodic drinkers had the highest likelihood of an increase in alcohol consumption, with 40% moving to the low-risk pattern. A notable proportion of participants returned to a lower severity pattern or transitioning out of drinking.

Conclusion: There are four distinct youth alcohol-use patterns. The high probability of transitioning to drinking during the secondary school years suggests the need for preventive interventions in earlier stages of use, before drinking becomes habitual.
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http://dx.doi.org/10.24095/hpcdp.39.8/9.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756132PMC
September 2019

Gene-based association analysis of survival traits via functional regression-based mixed effect cox models for related samples.

Genet Epidemiol 2019 12 10;43(8):952-965. Epub 2019 Sep 10.

Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, District of Columbia.

The importance to integrate survival analysis into genetics and genomics is widely recognized, but only a small number of statisticians have produced relevant work toward this study direction. For unrelated population data, functional regression (FR) models have been developed to test for association between a quantitative/dichotomous/survival trait and genetic variants in a gene region. In major gene association analysis, these models have higher power than sequence kernel association tests. In this paper, we extend this approach to analyze censored traits for family data or related samples using FR based mixed effect Cox models (FamCoxME). The FamCoxME model effect of major gene as fixed mean via functional data analysis techniques, the local gene or polygene variations or both as random, and the correlation of pedigree members by kinship coefficients or genetic relationship matrix or both. The association between the censored trait and the major gene is tested by likelihood ratio tests (FamCoxME FR LRT). Simulation results indicate that the LRT control the type I error rates accurately/conservatively and have good power levels when both local gene or polygene variations are modeled. The proposed methods were applied to analyze a breast cancer data set from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). The FamCoxME provides a new tool for gene-based analysis of family-based studies or related samples.
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http://dx.doi.org/10.1002/gepi.22254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829032PMC
December 2019

On estimands arising from misspecified semiparametric rate-based analysis of recurrent episodic conditions.

Stat Med 2019 11 20;38(25):4977-4998. Epub 2019 Aug 20.

Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Ontario, Canada.

Marginal rate-based analyses are widely used for the analysis of recurrent events in clinical trials. In many areas of application, the events are not instantaneous but rather signal the onset of a symptomatic episode representing a recurrent infection, respiratory exacerbation, or bout of acute depression. In rate-based analyses, it is unclear how to best handle the time during which individuals are experiencing symptoms and hence are not at risk. We derive the limiting value of the Nelson-Aalen estimator and estimators of the regression coefficients under a semiparametric rate-based model in terms of an underlying two-state process. We investigate the impact of the distribution of the episode durations, heterogeneity, and dependence on the asymptotic and finite sample properties of standard estimators. We also consider the impact of these features on power in trials designed to test intervention effects on rate functions. An application to a trial of individuals with herpes simplex virus is given for illustration.
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http://dx.doi.org/10.1002/sim.8345DOI Listing
November 2019

Testing the heritability and parent-of-origin hypotheses for ages at onset of psoriatic arthritis under biased sampling.

Biometrics 2020 03 19;76(1):293-303. Epub 2019 Aug 19.

School of Statistics and Management, Shanghai University of Finance and Economics, Shanghai, China.

The heritability and parent-of-origin effect hypotheses for chronic diseases can be evaluated by estimating and conducting inference about the parameters that measure the within-family dependences in disease onset times. We model the within-family associations in these times using a Gaussian copula whose correlation matrix accommodates the different pairwise family relationships. We derive score-type statistics to test the heritability and parent-of-origin effect hypotheses when the families selection protocol induces a sampling bias. We illustrate the use of the developed methods through an application to a motivating family study in Psoriatic arthritis and provide strong evidence of excessive paternal transmission of risk.
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http://dx.doi.org/10.1111/biom.13138DOI Listing
March 2020

A new perspective on loss to follow-up in failure time and life history studies.

Stat Med 2019 10 24;38(23):4583-4610. Epub 2019 Jul 24.

Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Ontario, Canada.

A framework is proposed for the joint modeling of life history and loss to follow-up (LTF) processes in cohort studies. This framework provides a basis for discussing independence conditions for LTF and censoring and examining the implications of dependent LTF. We consider failure time and more general life history processes. The joint models are based on multistate processes with expanded state spaces encompassing both the life history and LTF processes. Tracing studies are discussed as a means of investigating the presence of dependent censoring and providing valid estimates of transition intensities and state occupancy probabilities. Simulation studies and an illustration based on a cohort of individuals with systemic lupus erythematosus demonstrate the usefulness and properties of the proposed methods.
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http://dx.doi.org/10.1002/sim.8318DOI Listing
October 2019

Response to: 'Can biomarkers differentiate psoriatic arthritis from osteoarthritis?' by Tian .

Ann Rheum Dis 2020 09 4;79(9):e113. Epub 2019 Jul 4.

Department of Medicine, Rheumatology, University of Toronto, Toronto, Ontario, Canada

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http://dx.doi.org/10.1136/annrheumdis-2019-215762DOI Listing
September 2020

Dependence modeling for multi-type recurrent events via copulas.

Stat Med 2019 09 24;38(21):4066-4082. Epub 2019 Jun 24.

Department of Statistics and Actuarial Science, University of Waterloo, ON, Canada.

When several types of recurrent events may arise, interest often lies in marginal modeling and studying the nature of the dependence structure. In this paper, we propose a multivariate mixed-Poisson model with the dependence between events accommodated by type-specific random effects which are associated through use of a Gaussian copula. Such models retain marginal features with a simple interpretation, reflect the heterogeneity in risk for each type of event, and provide insight into the dependence between the different types of events. Semiparametric inference is proposed based on composite likelihood to avoid high dimensional integration. An application to a study of nutritional supplements in malnourished children is given in which the goal is to evaluate the reduction in the rate of several different kinds of infection.
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http://dx.doi.org/10.1002/sim.8283DOI Listing
September 2019

Score tests based on a finite mixture model of Markov processes under intermittent observation.

Stat Med 2019 07 10;38(16):3013-3025. Epub 2019 Apr 10.

Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Canada.

A mixture model is described, which accommodates different Markov processes governing disease progression in a finite set of latent classes. We give special attention to the setting in which individuals are examined intermittently and transition times are consequently interval censored. A score test is developed to identify genetic markers associated with class membership. Simulation studies are conducted to validate the algorithm, assess the finite sample properties of the estimators, and assess the frequency properties of the score tests. A permutation test is recommended for settings when there is concern that the asymptotic approximation to the score test is poor. An application involving progression in joint damage in psoriatic arthritis (PsA) provides illustration and identifies human leukocyte antigen markers associated with unilateral and bilateral sacroiliac damage in individuals with PsA.
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http://dx.doi.org/10.1002/sim.8155DOI Listing
July 2019

Serum-based soluble markers differentiate psoriatic arthritis from osteoarthritis.

Ann Rheum Dis 2019 06 25;78(6):796-801. Epub 2019 Mar 25.

Division of Rheumatology, Department of Medicine, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada

Objectives: We aimed to identify soluble biomarkers that differentiate psoriatic arthritis (PsA) from osteoarthritis (OA).

Methods: Markers of cartilage metabolism (cartilage oligomeric matrix protein [COMP], hyaluronan), metabolic syndrome (adiponectin, adipsin, resistin, hepatocyte growth factor [HGF], insulin, leptin) and inflammation (C-reactive protein [CRP], interleukin-1β [IL-1β], IL-6, IL-8, tumour necrosis factor alpha [TNFα], monocyte chemoattractant protein-1 [MCP-1], nerve growth factor [NGF]) were compared in serum samples from 201 patients with OA, 77 patients with PsA and 76 controls. Levels across the groups were compared using the Kruskal-Wallis test. Pairwise comparisons were made with Wilcoxon rank-sum test. Multivariate logistic regression analyses were performed to identify markers that differentiate PsA from OA. Receiver operating characteristic (ROC) curves were constructed based on multivariate models. The final model was further validated in an independent set of 73 PsA and 75 OA samples using predicted probabilities calculated with coefficients of age, sex and biomarkers.

Results: Levels of the following markers were significantly different across the three groups (p<0.001)-COMP, hyaluronan, resistin, HGF, insulin, leptin, CRP, IL-6, IL-8, TNFα, MCP-1, NGF. In multivariate analysis, COMP (OR 1.24, 95% CI 1.06 to 1.46), resistin (OR 1.26, 95% CI 1.07 to 1.48), MCP-1 (OR 1.10, 95% CI 0.07 to 1.48) and NGF (OR<0.001, 95% CI <0.001 to 0.25) were found to be independently associated with PsA versus OA. The area under the ROC curve (AUROC) for this model was 0.99 compared with model with only age and sex (AUROC 0.87, p<0.001). Similar results were obtained using the validation sample.

Conclusion: A panel of four biomarkers may distinguish PsA from OA. These results need further validation in prospective studies.
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http://dx.doi.org/10.1136/annrheumdis-2018-214737DOI Listing
June 2019