Random Patient Effect Research Articles

Diurnal and Daily Symptom Variation in Patients with End Stage Kidney Disease: An Ecological Momentary Assessment Study.

Patients with end-stage kidney disease (ESKD) on hemodialysis (HD) experience a high symptom burden which is compounded by unpredictable fluctuations in symptom severity. Few studies have used ecological momentary assessment (EMA) to determine how symptoms vary over time. This study aimed to characterize the diurnal and day-to-day variability in symptoms among HD patients. Patients enrolled in the Technology Assisted Collaborative Care (TĀCcare) trial rated the intensity of physical, cognitive, and mood symptoms using an automated telephone-administered version of the Daytime Insomnia Symptom Scale (DISS) at four time-points (morning, early afternoon, late afternoon, evening) for seven consecutive days at baseline. Confirmatory factor analysis (CFA) was used to verify the original four-factor solution for the DISS: sleepiness/fatigue (SF), alert cognition (AC), positive mood (PM), and negative mood (NM). Symptom domain scores were calculated for each time point and mixed modeling with random patient effects was used to examine differences in daily symptoms daily time points between HD and non-HD days after controlling for age, gender, race, and comorbidity burden. One hundred and sixty patients were enrolled (mean±SD age 58±14 years, 45% women, 52% White). Diurnal symptom variation existed; trends were non-linear and differed by HD vs. non-HD days. Day-to-day symptom variation also existed; patients endorsed better physical, cognitive, and mood states (i.e., higher AC and PM) as well as lower symptom burden (i.e., lower SF and NM) on non-HD days compared to HD days at all time-points. The greatest day-to-day mean differences (MDs) were observed in the early afternoon for all symptom domains: AC (MD=0.17 p<0.001), PM (MD=0.28, p<0.001), SF (MD=-0.66, p<0.001), and NM (MD=-0.26, p<0.001). Patients with ESKD demonstrate diurnal variation in symptoms and greater symptom burden on HD days compared to non-HD days, with the most extreme differences in symptom severity occurring in the early afternoon.

MP08-13 SUCCESSFUL ADOLESCENT VARICOCELECTOMY IMPROVES TOTAL MOTILE SPERM COUNT

You have accessJournal of UrologyCME1 May 2022MP08-13 SUCCESSFUL ADOLESCENT VARICOCELECTOMY IMPROVES TOTAL MOTILE SPERM COUNT Michael Kurtz, Raymond Lay, Tanya Logvinenko, Saafia Masoom, Ozge Yetistirici, and David Diamond Michael KurtzMichael Kurtz More articles by this author , Raymond LayRaymond Lay More articles by this author , Tanya LogvinenkoTanya Logvinenko More articles by this author , Saafia MasoomSaafia Masoom More articles by this author , Ozge YetistiriciOzge Yetistirici More articles by this author , and David DiamondDavid Diamond More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002530.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Management of the adolescent varicocele focuses on optimizing fertility potential, but to date there is limited data on the success of optimizing semen parameters for individual adolescent patients following varicocelectomy. We reviewed our database of over 1600 adolescent varicocele patients to find those with both pre-and postoperative semen analyses to determine the impact of varicocele correction. METHODS: 15 Tanner stage V patients with unilateral clinically apparent left-sided varicocele (12 grade III, 3 grade II) with pre-and postoperative semen analyses were identified. Mixed models were used to compare semen parameters pre- and post-varicocelectomy in patients with successful management. Random patient effect was used in the models to account for multiple semen analyses in patients. Model assumptions were verified. RESULTS: Complete elimination of the varicocele was achieved in 12/15 (80%) patients. Three patients had persistent varicocele (with down-grading in two) and declined further intervention. For those with successful varicocele correction total motile sperm count (TMSC) improved in 100% (Figure 1), with an average increase of 44.0 (95% CI: 18.7 – 69.3) in TMSC in post-varicocelectomy analyses compared to pre-varicocelectomy (p=0.0016). It went from abnormal (<20mln/cc) to normal (>=20 mln/cc) in 58% (7/12). It improved but remained abnormal in 25% (3/12). In 17% (2/12) it improved within normal range. Concentration improved significantly by 20.8 million /ml on average for the post-varicocelectomy group compared to pre-procedure (p=0.0036). For the three patients with persistent varicocele (Grades I, II and III) one had improved TMSC from abnormal to normal range and one had worsening of TMSC within normal range. CONCLUSIONS: Successful correction of adolescent varicocele reliably improves TMSC. In over half of cases an abnormal TMSC will normalize. Incomplete correction may result in improved TMSC, which should be assessed prior to re-intervention if abnormal semen parameters represented the surgical indication. These results support intervention for adolescent varicocele associated with abnormal semen parameters. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e130 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Kurtz More articles by this author Raymond Lay More articles by this author Tanya Logvinenko More articles by this author Saafia Masoom More articles by this author Ozge Yetistirici More articles by this author David Diamond More articles by this author Expand All Advertisement PDF DownloadLoading ...

Concussion Alters Dynamic Pupillary Light Responses in Children.

To investigate the impact of concussion on pupillary function in children by examining pupillometric parameters and assessing for differences in children reporting photosensitivity. Retrospective chart review was performed of pediatric patients referred for visual symptoms after concussion from 2017 to 2018 seen in a single academic outpatient clinic. Pupillometry data of 92 patients were included. Outcomes were compared to normative pediatric data from the same institution by 2-sample t tests. The association between photosensitivity and each outcome was assessed by use of linear mixed models with photosensitivity as a fixed effect and random patient effect. Outcomes of 181 eyes in 92 concussion patients were averaged by patient and compared to normative values in scotopic conditions. Concussion patients had an average age of 13.8 ± 2.64 years. Average constriction velocity (P = .0008), maximum constriction velocity (P = .0012), and average dilation velocity (P = .0034) were faster in concussion patients, whereas 75% recovery times (P = .0027) was increased. Photosensitivity did not significantly affect measured pupillary responses. Dynamic pupillary responses may be increased in pediatric concussion. Pupillometry may provide insight into the complex pathophysiological changes underlying pediatric concussion.

532-P: The Longitudinal Determinants of Diabetic Complications in the Pima Indians of Arizona

The 5 components of the metabolic syndrome (MetS) increase the likelihood of developing diabetes, heart disease, and stroke, but their association with neuropathy and diabetic kidney disease (DKD) is less understood. We examined the longitudinal association between the components of the updated National Cholesterol Education Program criteria for MetS, neuropathy and DKD in Pima Indians with type 2 diabetes, after substituting BMI for waist circumference. The primary outcome for neuropathy was the Michigan Neuropathy Screening Instrument index, for cardiovascular autonomic neuropathy (CAN) was the expiration/inspiration ratio, and for DKD was the Glomerular Filtration Rate. At baseline and during annual follow-up exams, participants underwent metabolic phenotyping and outcome measurements. Linear mixed effects models with a random patient effect were used to evaluate the associations between the number of MetS components and neuropathy, CAN, and DKD outcomes. We also examined mixed models for each outcome with individual MetS components. Between 11/1/2013 and 7/1/2019, we studied 141 Pima Indian subjects, who were followed an average of 3.2 years. The mixed effects models revealed a significant interaction between the number of MetS components and follow-up time for neuropathy (point estimate (PE): 0.07, CI: 0.02-0.11), indicating that the rate of neuropathy increases as the number of MetS components increases. Additionally, we found that neuropathy (year PE: 0.30, CI: 0.24,0.35) and DKD (PE: -14.2, CI: -16.8,-11.4), worsened over time, but CAN did not. The mixed models with individual MetS components revealed SBP was associated with each complication: neuropathy (PE: 0.23, CI: 0.07,0.39), CAN (PE: -0.02, CI: -0.03,-0.02) and DKD (PE: -10.2, CI: -15.4,-5.1). Neuropathy progression was the complication most affected by the number of MetS components. Neuropathy and DKD worsened during follow-up, emphasizing how quickly these complications can change within this population. Disclosure E.L. Reynolds: None. R.G. Nelson: None. G. Akinci: Advisory Panel; Spouse/Partner; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Speaker’s Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. R. Henn: None. A. Patterson: None. E.L. Feldman: Consultant; Self; Novartis Pharmaceuticals Corporation. B.C. Callaghan: None. Funding National Institutes of Health (R24DK082841, T32NS0007222, R01DK115687); Program for Neurology Research &amp; Discovery; Robert and Katherine Jacobs Environmental Health Initiative; Robert E. Nederlander, Sr. Program for Alzheimer’s Research; Sinai Medical Staff Foundation

Antidepressant Effect of the VA Weight Management Program (MOVE) Among Veterans With Severe Obesity.

Obesity is prevalent among users of Veteran's Health Administration services, where it is comorbid with depression, post-traumatic stress disorder, type 2 diabetes, cardiovascular disease, colon, and breast cancer. Among obese subjects, severe obesity represents a subpopulation with the highest risk of depression. We investigate the antidepressant effect of a local VA weight management program (Managing Overweight Veterans Everywhere - MOVE) among depressed veterans with severe obesity. In a 10-week prospective pilot study, 14 clinically depressed veterans with severe obesity were recruited from: (1) the 2-week residential based intense MOVE program (IMP) (N=7) and (2) the 10-week educational module of self-management MOVE program (SMP) (N=7). Subjects had a Beck Depression Inventory, 2nd edition (BDI-II) score> 12 and BMI> 40 or BMI> 35 with associated to comorbid conditions. Concurrent treatment for depression such as medications or psychotherapy was excluded. The primary efficacy endpoint was the change in BDI-II score form baseline to week 10. Analysis consisted of linear mixed model with baseline BDI-II score as a covariate, and level of MOVE intervention (IMP vs. SMP), time, and time by treatment interaction as fixed effects, and random patient effect. Pearson's correlation examined the relationships between clinical and demographic variables and change in severity of depression by BDI-II scores. Secondary outcomes include weight loss and energy expenditure. The sample was composed by 14 subjects (IMP=7; SMP=7) mostly unemployed (N=9), married (N=10), mid-aged (mean=58.2, SD=8.4), Caucasian (N=13), male (N=12), with recurrent depression (N=11), and a mean overall duration of current depressive episode of 13.5months (SD=10.2). Out of 14 participants; seven had a family history of mood disorder, two had previous psychiatric hospitalization, three had a previous suicidal attempt, and eight had a history of substance use disorder. There was a significant decrease in severity of depression among all 14 (F3,36.77=5.28; P<0.01); antidepressant effect favored the IMP compared to SMP at day 12 (F1,15.10=9.37, P=0.01) and week 6 (F2,27.34=4.26, P=0.03), but effect fell short of significance at week 10. The change in severity of depression measured by BDI-II score significantly correlated with total weight loss (r=-0.60; P=0.04) and daily energy expenditure at 12days (r=-0.67; P=0.01), week 6 (r=-0.59; P=0.03), and week 10 (r=-0.71; P=0.01). Depressed veterans with severe obesity improved their depressive symptoms by participating in the MOVE program. Veterans in the IMP had greater but short-term antidepressant effect as compared to educational intervention for obesity. Future studies with larger sample size may elucidate the underlying mechanisms of weight reduction to improve depression and, more importantly, sustain response among veterans with severe obesity.

Refined National Institutes of Health response algorithm for chronic graft-versus-host disease in joints and fascia

AbstractImplementation of the 2014 National Institutes of Health (NIH) response algorithm for joint/fascia graft-versus-host disease (GVHD) has identified real-world limits to its application. To refine the 2014 NIH response algorithm, we analyzed multicenter prospective observational data from the Chronic GVHD Consortium. The training cohort included 209 patients and the replication cohort included 191 patients with joint/fascia involvement during their course of chronic GVHD. Linear mixed models with random patient effect were used to evaluate correlations between response categories and clinician- or patient-perceived changes in joint status as an anchor of response. Analysis of the training cohort showed that a 2-point change in total photographic range of motion (P-ROM) score was clinically meaningful. The results also suggested that a change from 0 to 1 on the NIH joint/fascia score should not be considered as worsening and suggested that both the NIH joint/fascia score and total P-ROM score, but not individual P-ROM scores, should be used for response assessment. On the basis of these results, we developed an evidence-based refined algorithm, the utility of which was examined in an independent replication cohort. Using the refined algorithm, ∼40% of responses were reclassified, largely mitigating most divergent responses among individual joints and changes from 0 to 1 on the NIH joint/fascia score. The refined algorithm showed robust point estimates and tighter 95% confidence intervals associated with clinician- or patient-perceived changes, compared with the 2014 NIH algorithm. The refined algorithm provides a superior, evidence-based method for measuring therapeutic response in joint/fascia chronic GVHD.

Correlations between von Willebrand Factor Antigen Levels and Factor VIII Pharmacokinetics Are Similar across Different FVIII Products in Patients with Severe Hemophilia A

Background: Prophylactic treatment with replacement factor VIII (FVIII) is the standard of care for patients with severe hemophilia A to prevent bleeding and subsequent joint damage and chronic arthropathy. Because of variability in patient characteristics and clinical needs, it is recommended that prophylaxis is tailored to individual patient needs based on their baseline characteristics, bleeding history, and FVIII pharmacokinetic (PK) parameters. Endogenous levels of von Willebrand factor antigen (VWF:Ag) are known to influence the PK of FVIII. This analysis investigates the relationship between FVIII PK parameters and VWF:Ag levels, as well as between VWF:Ag levels and age, in patients with severe hemophilia A treated with various recombinant FVIII products using data obtained from multiple clinical trials. Patients/Methods: This integrated regression analysis is based on data with five FVIII products from six clinical trials. The products were: PEGylated recombinant FVIII BAY 94-9027 (damoctocog alfa pegol, Jivi®); sucrose-formulated recombinant FVIII (rFVIII-FS; Kogenate®-FS); BAY 79-4980 (liposomal version of Kogenate®-FS); unmodified full-length recombinant FVIII BAY 81-8973 (Kovaltry); and recombinant antihemophilic factor plasma/albumin-free method rAHF-PFM (octocog alfa, Advate®). The trials were: NCT01184820, NCT01029340, NCT00623727, NCT01233258, NCT02483208, and NCT01580293. PK parameters were estimated by means of a non-compartmental analysis based on densely sampled single-dose profiles measured by one-stage and chromogenic assays, and following a dose of 25-60 IU/kg. The primary regression analysis was performed using the log-transformed PK parameters (half-life [t1/2], clearance [CL], and dose-normalized area under the curve [AUCnorm]) as dependent variables and the VWF:Ag levels as the independent variable in a mixed model including fixed treatment effects and random patient effects. In addition, the impact of age on VWF:Ag levels was investigated. One-stage assay results are reported. Results based on the chromogenic assay were in line with those reported for the one-stage assay. Results: Data from 104 patients from six studies were used to investigate the relationship of the dose-independent PK-parameter, t1/2 vs VWF:Ag levels, and of VWF:Ag levels vs age. Median age was 31 years (range 12-64 years). For the analyses of the PK parameters AUCnorm and CL, data from 77 patients from five studies were analyzed. Median age was 32 years (range 12-64 years). Some patients participated in multiple studies. The primary regression analyses across all products and studies on the log-transformed PK parameters showed significant associations between PK parameters and VWF:Ag levels. Significant positive correlations vs VWF:Ag levels were observed for t1/2 (n = 155 observations in 104 patients, P &amp;lt; 0.001) and AUCnorm (n = 117 observations in 77 patients, P &amp;lt; 0.001), resulting in a negative correlation with CL (Figure 1). Other factors, such as age and the interaction of treatment with the VWF:Ag-PK effect, were found to be redundant and were not included in the final model. Analysis of VWF:Ag levels vs age using a simple linear regression that did not incorporate the dependencies of multiple observations in patients, revealed a positive correlation between age and VWF:Ag levels (Spearman coefficient , r = 0.290 [P = 0.0029]; Pearson coefficient, r = 0.334 [P = 0.0005]). Comparable results were observed in a mixed model with random patient effects. Conclusions: In this combined analysis across five FVIII products, FVIII PK parameters (t1/2, AUCnorm, and CL) were significantly correlated with endogenous VWF:Ag levels which were also correlated with age. Moreover, while there were differences in the average PK parameters between products (represented by the intercept for treatment), all five FVIII products demonstrated similar VWF-PK relationships. It is well known that a patient's VWF:Ag level influences the PK of rFVIII, but this analysis suggests that the quantitative relationship between FVIII PK and VWF:Ag is similar for modified and unmodified FVIII products. This finding can be used, for example, to support selection of adequate treatment regimens when a patient is switching rFVIII product. Disclosures Maas Enriquez: Bayer: Employment. Delesen:Bayer: Employment. Solms:Bayer: Employment, Equity Ownership. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Octapharma: Honoraria; CSL Behring: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Berntorp:Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Shire: Consultancy, Honoraria, Research Funding; Sobi/Bioverativ: Research Funding; Octapharma: Consultancy, Honoraria.

Diurnal, Seasonal, and Monthly Variationsin Ventricular Arrhythmias inPatients With Implantable Cardioverter-Defibrillators.

The aim of this study was to assess the variations in ventricular arrhythmia (VA) occurrence according to seasons, months of the year, days of the week, and the time of day in a large implantable cardioverter-defibrillator patient population. Limited data exist on how VA occurrence varies as a function of time. Data from 6 prospective studies were pooled to assess VA frequency over time. All adjudicated episodes of VAs≤500ms were included. VA distribution as a function of hour, day, month, and season were assessed through the construction of 4 negative binomial models. The models included a random patient effect and offset for days spent in each time period. Among 3,969 patients, 7,126.8 cumulative device-years with an average follow-up duration of 1.8±1.4years/patient were analyzed. VA occurrence was higher in the spring than the summer (0.86% vs. 0.70%; p= 0.009) but not significantly different from the fall (0.74%; p= 0.069) or winter (0.84%; p= 0.732). The estimated probability of occurrence of at least 1 VA episode in each 1-h block during the hours of 8 am to 10 pm over 365days (0.10% to 0.12%) was higher (estimated 35% to 63% higher) than the referent period of midnight to 1 am (0.07%). No significant variations in VA occurrence were observed according to weekday and individual months of the year. Significantly higher VA occurrence in the spring and during the hours of 8 am to 10 pm were observed.Additional studies are needed to further understand the reasons for these observations, which may involvevariations in temperature or differences in catecholamine triggers.

Effects of Primary Alveolar Grafting on Alveolar Bone Thickness in Patients With Cleft Lip and Palate.

The purpose of this study was to compare alveolar bone thickness around the teeth adjacent to the cleft using cone beam computed tomography (CBCT) in patients with cleft lip and palate (CLP) who underwent primary alveolar grafting (PAG) as compared with CLP waiting for secondary alveolar grafting (SAG) and to determine the associations with other factors such as the patient's age, sex, and type of cleft. CBCTs of 39 CLP patients were divided into either group 1 (PAG, N = 11) or group 2 (SAG, N = 28). Measurements of bone thickness around the closest tooth to the cleft were performed on the axial sections on each subject's CBCT at 3, 6, and 9 mm apical to the cementoenamel junction along the root length. Intraclass correlation coefficients and Bland-Altman plots were used to evaluate intrarater reliability. Bone measurements with 95% confidence intervals for the mean were estimated using analysis of variance models with a random patient effect to account for correlation among multiple measurements within a patient. Similar models were used to test the associations of age, sex, and type of the graft with the bone measurements. No statistically significant associations of the factors were found with mesial or distal bone measurements. Buccal bone thickness was significantly greater only at 9 mm in the primary bone graft subjects compared with secondary bone graft subjects (P = 0.009). Unilateral cleft subjects showed significantly greater buccal bone thickness at the level of 9 mm compared with bilateral cleft subjects (P = 0.046) and lingual bone thickness at the level of 6 mm (P = 0.0026) and 9 mm (P = 0.0096). In conclusion, PAG does not add benefits to the bone width on the cleft sides of the closest teeth to the cleft as compared with children with CLP who have not undergone alveolar grafts yet.

Occurrence of Progressive Bone Loss Around Anodized Surface Implants and Resorbable Blasting Media Implants: A Retrospective Cohort Study.

This study evaluates occurrence of progressive bone loss (PBL) around implants with different implant surfaces. Retrospective examination of 2,517 implants was performed in 903 patients, including 1,147 anodized-surface implants in 454 patients and 1,370 resorbable blasting media (RBM)-surface implants in 449 patients, which were placed from January 2006 to December 2010. Through regular check-up radiographs and records, presence of PBL (up to >50% of fixture length) was investigated. Implant removal for any reason was regarded a failure. In total, 2,186 implants (979 anodized implants and 1,207 RBM implants) in 793 patients were included in this study. PBL was more frequently observed among anodized implants (n = 36 in 21 patients; 4%) than among RBM implants (n = 19 in 14 patients; 2%), and this difference was statistically significant (P <0.001). Occurrence of PBL was significantly influenced by surface modification and implant diameter (odds ratio [OR] of anodized surface = 4.40, 95% confidence interval [CI] = 1.78 to 10.89, P = 0.001; OR of wide implants = 9.62, 95% CI = 1.13 to 81.68, P = 0.038; determined by mixed-effects logistic regression analysis with random patient effect). However, total survival rate was significantly influenced by implant diameter and not by surface modification (P = 0.019), although effect of implant diameter was observed to be significant on anodized implants (P = 0.030). Implant surface modification and implant diameter are significantly associated with occurrence of PBL.

Racial differences in health-related quality of life and functional ability in patients with gout.

To compare the health-related quality of life (HRQOL) and the functional ability by race in patients with gout. In a 9-month prospective cohort multicentre study, patients with gout self-reported race, dichotomized as Caucasian or African American (others excluded). We calculated HRQOL/function scores adjusted for age, study site and college education for Short Form-36 (SF-36; generic HRQOL), Gout Impact Scale (GIS; disease-specific HRQOL) and HAQ-disability index (HAQ-DI; functional ability). Longitudinally adjusted scores were computed using multivariable mixed-effect regression models with a random patient effect and fixed sequential visit effect (3-monthly visits). Compared with Caucasians (n = 107), African Americans (n = 60) with gout were younger (61.1 vs 67.3 years) and had higher median baseline serum urate (9.0 vs 7.9 mg/dl) (P < 0.01). African Americans with gout had worse HRQOL scores on three SF-36 domains, the mental component summary (MCS) and two of the five GIS scales than Caucasians [mean (se); P ⩽ 0.02 for all]: SF-36 mental health, 39.7 (1.1) vs 45.2 (0.9); SF-36 role emotional, 42.1 (4.2) vs 51.4 (4.2); SF-36 social functioning, 36.0 (1.1) vs 40.0 (0.9) (P = 0.04); SF-36 MCS, 43.2 (3.1) vs 50.0 (3.2); GIS unmet treatment need, 37.6 (1.6) vs 31.5 (1.4); and GIS concern during attacks, 53.3 (3.7) vs 47.4 (3.7). Differences between the respective HAQ-DI total scores were not statistically significant; 0.98 (0.1) vs 0.80 (1.0) (P = 0.11). Racial differences in SF-36 mental health, role emotional and MCS scales exceeded, and for HAQ-DI approached, the minimal clinically important difference thresholds. African Americans with gout have significantly worse HRQOL compared with Caucasians. Further research is necessary in the form of studies targeted at African Americans on how best to improve these outcomes.

Bias of complete-case analysis of williams square crossover designs when data are missing not at random

A Williams square is a particular type of Latin square that is widely used for crossover trials when comparing t treatments over t treatment periods. As with most forms of clinical trials, crossover trials do not always obtain all the observations prescribed in the design and the analyst has to deal with missing data. An intention-to-treat (ITT) analysis would analyse the available observations and, if these were continuous, a linear model with random patient effects and fixed effects for period and treatment would often be used. However, for a crossover design a stronger argument might be made for analysing only complete cases than would be possible for a parallel group design. Crossovers compare all treatment in each patient and if, e.g., an observation was missing because the patient could not tolerate the administered treatment, then including a patient who could not tolerate all treatments may not be the most pertinent basis for inference. While a complete-case analysis may be a plausible alternative to an ITT analysis, there are likely to proponents in favour of both strategies. In this work we compare the approaches, principally by working out the bias in a complete-case analysis when data are missing not at random. Attention is focussed on a four-period Williams design and the work is discussed in the context of the TOMADO trial (Thorax, 69, 938-945) of mandibular advancement devices for the treatment of sleep apnoea.

Abstract P5-01-07: Fidelity of FDG-PET in breast cancer: Reproducibility at multiple sites

Abstract Introduction Breast cancer is a common, treatable malignancy, with frequent metastasis to bone. Patients with bone-dominant disease are often excluded from clinical trials due to a lack of RECIST "measurable" disease. FDG-PET can help quantitatively measure multiple tumor sites, and assay disease activity in bone. However, the reproducibility of FDG-PET at multiple sites is unproven. We sought to pilot alignment of clinical protocols prior to imaging, phantom testing and then repeat patient scans, in patients undergoing clinical FDG-PET to test the fidelity of quantitative FDG-PET imaging. Methods After determination and alignment of clinical protocols, and serial successful phantom imaging, ten female patients with metastatic breast cancer underwent paired FDG-PET/CT test-retest studies with no more than 15 days between scans and without interim change in treatment. Seven patients were studied in the same scanner and 3 patients were studied in 2 different scanners in our clinical network. Each PET/CT scanner’s quantitative performance was monitored with NIST-traceable reference sources to ensure proper calibration. Images were interpreted and SUV metrics were estimated at a central lab. Linear mixed models with a random intercept were fitted to compare test-retest differences in multiple lesions per patient. Results SUVmax was assessed in a total of 68 lesions (52 bone, 16 other sites). Average SUVmax ranged from 2.3 to 18.2 (mean±SD = 5.7±2.6) per patient. The median SUVmax difference was 0.25 (5%) for 35 lesions imaged twice in the same scanner, and was 0.01 (0.2%) for 33 lesions imaged in two different scanners. In a linear mixed-effects model with random patient effects, there was no difference in average percentage SUV difference for the same scanner versus different scanners (p=0.70). In the same model, the absolute percentage difference in SUVmax for bone lesions was estimated as 6 percentage points lower than for other sites (p=0.002, 95% confidence interval 2%-10%). Conclusions If PET/CT systems are carefully calibrated, and imaging protocols are consistent, then variability associated with FDG SUVmax between scans is similar to prior test-retest studies. Bone lesions appear to have tighter reproducibility than soft tissue lesions. Clinical trials that utilize quantitative PET/CT imaging throughout a network of calibrated PET/CT scanners could increase patient recruitment and improve confidence in trial results. Accrual is ongoing and results will be updated. Research support Supported by NIH grant U01-CA148131 and NCI-SAIC Contract 24XS036-004. Citation Format: Hannah M Linden, Jennifer Specht, Lanell Peterson, Brenda Kurland, Andrew Shields, Darrin Byrd, Alena Novakova, Rebecca Christofel, Mark Muzi, David Mankoff, Kinahan Paul. Fidelity of FDG-PET in breast cancer: Reproducibility at multiple sites [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-01-07.

SOURCE-SPECIFIC AIR POLLUTION AND SYSTEMIC INFLAMMATION IN ISCHEMIC HEART DISEASE PATIENTS

Background and Aims: Associations between particulate air pollution (PM) and cardiovascular health have been observed in numerous studies. Exposure to PM can accelerate systemic inflammation, which has been hypothesized to play an important role in the development of cardiovascular disease. Our aim was to evaluate the association between source-specific PM and systemic inflammation among ischemic heart disease patients. Methods: Fifty-two ischemic heart disease patients were followed for six months with biweekly clinical visits (minimum of three) including a blood-withdrawal in Kotka, Finland, between November 2005 and May 2006. Blood levels of high-sensitive Creactive protein (CRP) and fibrinogen were determined to be used as indicators of systemic inflammation. Daily levels of air pollution were measured at a central outdoor measurement site. Source-apportionment for fine particles (&lt; 2.5 µm in diameter) was conducted using positive matrix factorization 3.0.2.2. by the U.S. Environmental Protection Agency. Immediate and delayed associations of source-specific air pollution with levels of fibrinogen and log-transformed CRP were analyzed using mixed models with random patient effects adjusting for time-trend, temperature and relative humidity. Results: There were 507 successful repeated clinical visits in total. Looking at 5-day average concentration, CRP had stronger association with air pollution than fibrinogen. The %-changes for CRP were 2.9% (95%-confidence interval (CI): 0.3 to 5.5%) for long-range transported PM, 31.1% (95%-CI: -6.4 to 83.8 %) for traffic emissions, 2.3% (95%-CI: 0.2 to 4.5%) for biomass burning and -16.1% (95%-CI: -27.2 to -3.3%) for pulp industry per 1µg m-3 increase in pollutant concentration. We found no association for seasalt. Conclusions: Our results suggest that several sources of ambient air pollution are associated with systemic inflammation, a risk factor for coronary heart disease.

Guidelines for calculating sample size in 2x2 crossover trials : a simulation study

In crossover trials, patients receive two or more treatments in a random order in different periods. The sample size determination is often an important step in planning a crossover study. This paper concerns sample size calculations in 2x2 crossover trials, with random patient effects and no interaction between the treatment and the patient under two scenarios, namely the exact and the large sample size approaches. Simulation was carried out for determining the sample size for both scenarios. For varying parameter values, simulation was used for generating samples of the required size and examining whether the significance level and power of the tests are maintained. The results indicate that when the sample size was ≤ 5, neither method maintained error rates and when the sample size was >5 and 12 both methods maintained error rates. In addition it was found that a saving in sample size can be achieved depending on the extent of the correlation between the observations on the same patient. The simulation results indicate that crossover studies should not be conducted when the anticipated sample size is ≤ 5 and when a sample size of >5 and Keywords: Crossover trial, exact method, large sample method, sample size calculation, simulation. Doi: 10.4038/jnsfsr.v39i1.2929 J.Natn.Sci.Foundation Sri Lanka 2011 39 (1):77-89

Multivariate Failure Time Analysis when only the Time to First Failure is Observed

We propose a log-linear mixed model to assess covariate effects on the unobservable, catheter-related time-until-infection (TUI), utilizing the observable time-until-first-infection (TUFI). The model assumes that both log (TUI) and the common (random) patient effect follow an extreme value distribution, and TUIs of the same patient are conditionally independent. This model enables the assessment of covariate effects on TUI, accounting for both patient-level (age) and catheter-level (e.g., difficulty of insertion) covariates and the within-patient correlation. The efficient likelihood estimators of fixed-effects and scale parameters of random effects are shown to be consistent and asymptotically normal and appear to perform well in simulations. The methods are illustrated using an example.

Air temperature and inflammatory and coagulation responses in men with coronary or pulmonary disease during the winter season

Background and ObjectiveAir temperature changes are associated with increased cardiovascular and respiratory risk, but the roles of inflammatory and coagulation markers are not well understood. We investigated the associations between...

Air Temperature and Inflammatory and Coagulation Responses in Patients with Coronary or Pulmonary Diseases

ISEE-0195 Background and Objective: Air temperature changes have been associated with increased cardiovascular and respiratory risk, but the role of inflammation and coagulation markers in these relationships is not well understood. We investigated the associations between temperature and several blood markers in individuals with coronary heart disease (CHD) and pulmonary disease (PD). Methods: Two panel studies were conducted in Erfurt, Germany, in two subsequent winters. In total, 578 and 381 repeated blood measurements from 57 CHD and 38 PD patients were collected, respectively. Data on patient characteristics and disease history were gathered at the baseline visit. Meteorological data were collected from existing networks. Associations were analyzed using additive mixed models with random patient effects. Effect modification by diabetes status was investigated only in CHD patients, as only two diabetic individuals were part of the PD panel. Results: Mean daily air temperature varied between −13°C and 16°C in both study periods. A 10° decrease in the 5-day-average of temperature before the blood withdrawal led to an increase in fibrinogen (%-change from the mean: 5.5%; 95%-confidence interval (CI): [1.3%; 9.7%]) and platelet counts (3.0%; 95%-CI: [0.6%; 5.5%]), and to no change in C-reactive protein in PD patients, whereas for CHD patients a decrease was observed. A two day delayed increase in factor VII in association with a temperature decrease was seen in CHD patients (4.9%; 95%-CI: [0.7%; 9.2%]), while PD patients showed no effect. The effects in CHD patients without diabetes were similar to those of the PD patients, whereas diabetic CHD patients showed a strong effect (12.1%; 95%-CI: [5.8%; 18.9%]). Conclusions: The present study suggests that a temperature decrease is associated with a change in several blood parameters. It can only be speculated that the partly opposite findings in CHD and PD patients might be influenced by their differing diabetic status.

Relapse–remission and remission–relapse switches in rheumatoid arthritis patients were modeled by random effects

Objective To compare statistical models for the analysis of two-state disease processes. Study Design and Setting A two-armed randomized trial of patients with early rheumatoid arthritis (RA) treated by either combination therapy (sulfasazaline, methotrextate, prednisolone) or monotherapy (sulfasazaline). Disease activity (remission or relapse) was analyzed with the logistic regression model, the proportional hazards regression model, and the continuous-time Markov process model for panel data. The dependence among the switching times was studied by (1) including correlated normal random patient effects for the relapse–remission and remission–relapse switching probabilities; (2) assuming the population to be a mixture of patients responsive and nonresponsive to therapy; (3) including separate parameters for the first and subsequent relapse–remission switch; and (4) combining (1) and (3). The four approaches were compared using parametric bootstrap checks. Results The logistic regression model, the proportional hazards regression model, and the continuous-time Markov process model for panel data yielded similar combination therapy effects. The inclusion of random patient effects (approaches 1 and 4) gave the best fit to the observed disease activity pattern. Conclusion Models with correlated random effects can provide a satisfactory fit to two-state disease patterns.

Air Temperature and Inflammatory Responses in Myocardial Infarction Survivors

Temperature changes have been associated with increased cardiovascular risk, but the role of inflammatory markers in this relationship is not well understood. The objective of this study was to analyze the association between air temperature and C-reactive protein, interleukin-6 and fibrinogen in postmyocardial infarction patients. In a multicenter panel study, the 3 inflammatory blood markers were measured repeatedly. In total, 5813 blood samples in 1003 subjects were collected in 6 European cities representing different climates. Data on patient characteristics and disease history were gathered at the baseline visit. Meteorologic data were obtained from the city-specific network stations. The association was analyzed using a semiparametric model with random patient effects. A 10 degrees C decrease in the 5-day-average of air temperature before the blood withdrawal was associated with a 4% increase in C-reactive protein (4.3% [95% confidence interval = 0.2% to 8.1%]). Correspondingly, an increase of interleukin-6 was observed for the same time window (3.3% [0.1% to 6.3%]) whereas fibrinogen showed an increase of 1.3% (0.2% to 2.4%) with a lag of 3 days. A decrease in air temperature, particularly the average temperature of the last 5 days, was associated with an increase in both C-reactive protein and interleukin-6, whereas fibrinogen seemed to react to temperature changes after 3 days. In susceptible patients this might lead to an additional risk for cardiovascular events and suggests a biologic mechanism for the observed seasonal variation in death from ischemic heart disease and stroke in the elderly.