scholarly journals Two-Phase, Generalized Case-Control Designs for the Study of Quantitative Longitudinal Outcomes

2019 ◽  
Vol 189 (2) ◽  
pp. 81-90
Author(s):  
Jonathan S Schildcrout ◽  
Sebastien Haneuse ◽  
Ran Tao ◽  
Leila R Zelnick ◽  
Enrique F Schisterman ◽  
...  
Keyword(s):  
Phase 1 ◽  
Epidemiologic Study ◽  
Health Study ◽  
Time Varying ◽  
Genetic Associations ◽  
Two Phase ◽  
Longitudinal Outcomes ◽  
Covariate Data ◽  
Longitudinal Outcome ◽  
Study Designs

Abstract We propose a general class of 2-phase epidemiologic study designs for quantitative, longitudinal data that are useful when phase 1 longitudinal outcome and covariate data are available but data on the exposure (e.g., a biomarker) can only be collected on a subset of subjects during phase 2. To conduct a study using a design in the class, one first summarizes the longitudinal outcomes by fitting a simple linear regression of the response on a time-varying covariate for each subject. Sampling strata are defined by splitting the estimated regression intercept or slope distributions into distinct (low, medium, and high) regions. Stratified sampling is then conducted from strata defined by the intercepts, by the slopes, or from a mixture. In general, samples selected with extreme intercept values will yield low variances for associations of time-fixed exposures with the outcome and samples enriched with extreme slope values will yield low variances for associations of time-varying exposures with the outcome (including interactions with time-varying exposures). We describe ascertainment-corrected maximum likelihood and multiple-imputation estimation procedures that permit valid and efficient inferences. We embed all methodological developments within the framework of conducting a substudy that seeks to examine genetic associations with lung function among continuous smokers in the Lung Health Study (United States and Canada, 1986–1994).

scholarly journals Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis

2014 ◽  
Vol 74 (7) ◽  
pp. 1387-1393 ◽  
Author(s):  
A Cortes ◽  
W P Maksymowych ◽  
B P Wordsworth ◽  
R D Inman ◽  
P Danoy ◽  
...  
Keyword(s):  
New York ◽  
Ankylosing Spondylitis ◽  
Phase 1 ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Two Phase ◽  
Radiographic Severity ◽  
Cyclooxygenase 1 ◽  
Prostaglandin Endoperoxide Synthase ◽  
Top 40

ObjectiveTo identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS).MethodWe studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon–intron boundaries, and 5 kb flanking DNA in the 5′ and 3′ UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into ‘mild’ and ‘severe’ groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration.ResultsExperiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10−5), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10−3). There was no observed association between radiographic severity and HLA-B*27.ConclusionsThese findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.

scholarly journals Patterns of Sedentary Behavior in a Community-Based Cohort of Older Adults

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 790-790
Author(s):  
Dori Rosenberg ◽  
Rod Walker ◽  
Mikael Anne Greenwood-Hickman ◽  
KatieRose Richmire ◽  
John Bellettiere ◽  
...  
Keyword(s):  
Older Adults ◽  
Epidemiologic Study ◽  
Epidemiologic Studies ◽  
Community Based ◽  
Covariate Data ◽  
Self Rated Health ◽  
Measurement Protocol ◽  
Sleep Logs ◽  
Hispanic White ◽  
Difficulty Walking

Abstract Few epidemiologic studies have examined device-measured sitting patterns by demographics and health status. The Adult Changes in Thought (ACT) study is an on-going epidemiologic study of adults age ≥65 years. We conducted a sub-study that added a thigh-worn activPAL device and sleep logs for 7 days to the measurement protocol. A total of 997 had valid wear time (≥4 days with 10-20 hours of data per day) and covariate data. activPAL sedentary pattern measures included number of sitting bouts lasting 30 minutes or more and mean sitting bout duration. On average, participants (56% female, 57% &gt; age 75, 89% non-Hispanic white) sat in bouts lasting 17 minutes (SD = 12) and had 5.9 (SD = 1.7) bouts of sitting lasting 30 minutes or more. Participants who were older, were male, had obesity, had worse self-rated health, had depression, and had difficulty walking had longer sitting bouts and more prolonged bouts.

Endometrial Adenocarcinoma in SurePath™ Cervical Samples: Cytological Features Revisited

2016 ◽  
Vol 60 (1) ◽  
pp. 46-52 ◽  
Author(s):  
Nalini Gupta ◽  
John Crossley ◽  
Nick Dudding ◽  
John H.F. Smith
Keyword(s):  
Phase 1 ◽  
Endometrial Adenocarcinoma ◽  
Nuclear Chromatin ◽  
Phase 2 ◽  
Cervical Lesions ◽  
Two Phase ◽  
Endometrial Cells ◽  
Phase Study ◽  
Cytological Features ◽  
Liquid Based Cytology

Objective: The cytomorphological criteria of malignant endometrial lesions in cervical samples are less well described than those of cervical lesions. We wished to investigate if there were features in SurePath™ liquid-based cytology samples that would facilitate more accurate differentiation between benign and malignant endometrial cells. Study Design: This was a two-phase study, with a review of all SurePath™ samples reported as endometrial adenocarcinoma (n = 42) evaluating 12 cytological features in the first phase. In phase 2 (test set), all initial cases plus an additional 83 cases were reviewed using these 12 cytological features to predict the outcome. Results: Out of 12 cytological features evaluated in phase 1 (training set), nuclear chromatin pattern, apoptotic bodies and tingible body macrophages were found to be the most significant features determining malignant histological outcome. These 12 cytological features were re-evaluated in phase 2 (n = 125). Of 125 cases, 54 had a benign and 71 had a malignant or premalignant histological outcome, with a positive predictive value of 56.8%. Conclusion: Granular nuclear chromatin, tingible body macrophages and apoptosis in the background are the most significant factors in determining whether endometrial cells present in cervical samples represent malignancy or are benign. Using these features, relatively accurate predictions of endometrial pathology can be made.

166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2684-2691 ◽  
Author(s):  
Sergio Giralt ◽  
William Bensinger ◽  
Mark Goodman ◽  
Donald Podoloff ◽  
Janet Eary ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
High Dose ◽  
Two Phase ◽  
Hematopoietic Stem

Abstract Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation. (Blood. 2003;102:2684-2691)

A Framework for Implementing Lean Manufacturing System in Small and Medium Enterprises

2011 ◽  
Vol 110-116 ◽  
pp. 3997-4003 ◽  
Author(s):  
Jirapat Wanitwattanakosol ◽  
Apichat Sopadang
Keyword(s):  
Lean Manufacturing ◽  
Manufacturing System ◽  
Job Shop ◽  
Small And Medium Enterprises ◽  
Phase 1 ◽  
Optimization Technique ◽  
Value Stream Mapping ◽  
Two Phase ◽  
Make To Order ◽  
Medium Enterprises

—In this paper, a conceptual framework to apply many techniques for implementing lean in the high-variety low-volume (HVLV) environment is presented. Lean production has increasingly being implemented as a potential solution for many organizations. Anyway, the lean formula is applicable directly only to the make-to-stock business, but the make-to-order (MTO) product environment has to adapt lean manufacturing principle. The method of this paper has a two-phase quantitative framework to transform small and medium enterprises (SMEs) to be lean. Phase 1 has three interrelated components: (1) re-engineering an organization by using the power of computer simulation combined with business process. (2) Value stream mapping (VSM) is used to create a map of both value and waste in a given process. This tool has also a main drawback for job shop facility because many value streams are composed of hundreds of industrial parts and products. (3) Integrative supplier relationship is one of the most critical factors to maintain an advantage in the increasing levels of competition. Phase 2 performs a just in time production schedule by using ant colony optimization technique combines with a simulation tool. The aims of this paper are to develop a suitable lean manufacturing system for SMEs and to study the performance of the system for improving effectiveness. The result shows how to combine lean concept with simulation optimization, the step of this framework to obtain the optimization solution.

Safety and unique pharmacokinetic profile of ARX788, a site-specific ADC, in heavily pretreated patients with HER2-overexpresing solid tumors: Results from two phase 1 clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1038-1038
Author(s):  
Sara A. Hurvitz ◽  
Haeseong Park ◽  
Sophia Frentzas ◽  
Catherine M. Shannon ◽  
Katharine Cuff ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Salivary Gland Cancer ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Two Phase ◽  
Site Specific ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
A Site

1038 Background: ARX788 is a site-specific, homogeneous, and highly stable ADC. The payload AS269 is conjugated to the synthetic amino acids para-acetylphenylalanine (pAF) in a humanized anti-HER2 mAb. ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies. Here we present the phase 1 clinical data evaluating the safety, antitumor activity, and PK of ARX788 in advanced solid tumors. Methods: The standard 3+3 design (0.33 - 1.5 mg/kg; Q3W or Q4W) is used to determine the MTD and/or RP2D in two phase 1 studies in HER2-positive solid tumors in U.S. and Australia (ACE-Pan tumor-01) and in HER2-positive breast cancers in China (ACE-Breast-01). The efficacy endpoints include ORR and DCR. Intensive PK sampling in first 3 cycles is performed to characterize serum PK profiles of ARX788, total Ab, and pAF-AS269. Results: 69 and 34 heavily pretreated patients received ARX788 monotherapy in the ACE-Breast-01 (median 6 prior lines of therapy) and ACE-Pan tumor-01 trial (including breast, gastric/GEJ, NSCLC, ovarian, urothelial, biliary track, endometrial, and salivary gland cancer) respectively. Dose escalation for both studies have been completed with no DLT reported. MTD has not been reached. ARX788 was generally well tolerated with most AEs being grade 1 or 2. The most common grade >3 AEs include ocular AEs (5.7 %) and pneumonitis (4.3%) in the ACE-Breast-01 trial; pneumonitis (2.9%) and fatigue (2.9%) in the ACE-Pan tumor-01 trial. Low systemic toxicities in terms of the incidence rate and grade (as shown in table). No treatment-related death. In the 1.5 mg/kg cohort, ORR was 74% (14/19) and 67% (2/3) for ACE-Breast-01 and ACE-Pan tumor-01, respectively. DCR was 100%. Median DOR or median PFS has not been reached. PK profiles for total antibody and ARX788 were generally comparable across all dose levels. Mean T1/2 for ARX788 and total antibody had approximately 100 hours at the dose of 1.5 mg/kg. Serum pAF-AS269 concentrations peaked with a median time of 168 h. Serum exposure of pAF-AS269 was low with the Cmax and AUC at cycle 1 being approximately 0.1% and 0.18% of those for ARX788 on a molar basis, respectively. Conclusions: High stability of ARX788 and low serum exposure of pAF-AS269 may underlie the low systemic toxicity, which differentiates it from other ADCs. Clinical trial information: NCT032550070 .[Table: see text]

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