Oak Creek, WI, United States
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Berg R.L.,Biomedical Informatics Research Center
Clinical Medicine and Research | Year: 2013

Objective: Potential vitamin B12 deficiency is a common clinical diagnostic problem, and many providers have a low threshold for initiating therapy. The goal of this study was to systematically evaluate current practice patterns regarding the laboratory evaluation of suspected vitamin B12 deficiency. Methods: This retrospective study reviewed the electronic medical records of 192 patients initiated on intramuscular vitamin B12 injections. Results: Only 12 patients had objectively documented hematologic responses: decrease of mean corpuscular volume by ≥5 fL with stable or improved hemoglobin. Another 5 patients had equivocal hematologic responses. There was one plausible neurologic response. Thus, only 18 (9.4%) of 192 patients had data supportive of a clinical response. In these 18 patients, the baseline serum B12 level was ≤107 pg/mL; only 3 patients also had a baseline serum methylmalonic acid level, which was ≥1.29 μmol/L in all 3 patients. Conclusions: Currently, only a small minority of patients initiated on intramuscular vitamin B12 supplementation derive any meaningful clinical benefit. Furthermore, current testing recommendations for vitamin B12 deficiency are usually not followed. Up-front ordering of a diagnostic testing cascade is recommended to improve compliance; an example is presented with decision points chosen to improve specificity for clinically evident vitamin B12 deficiency without loss of sensitivity. Ultimately, a better understanding of vitamin B12 physiology is needed to develop and evaluate laboratory tests that more accurately reflect true intracellular vitamin B12 status. ©2013 Marshfield Clinic.


McKiernan F.E.,Center for Bone Disease | Shrestha L.K.,The University of Oklahoma Health Sciences Center | Berg R.L.,Biomedical Informatics Research Center | Fuehrer J.,Biomedical Informatics Research Center
Osteoporosis International | Year: 2014

Summary: The temporal evolution of a low serum alkaline phosphatase value may relate to its cause. Precipitous lowering of serum alkaline phosphatase below the lower range of normal is uncommon and may indicate severe physiologic stress and increased short-term mortality. Introduction: The differential diagnosis of a low serum alkaline phosphatase (ALP) value (hypophosphatasemia) is wide ranging, anecdotal, and unfamiliar. The temporal evolution of hypophosphatasemia may relate to its cause. The purpose of this study is to report conditions and circumstances associated with precipitous lowering of serum ALP below the lower range of normal. Methods: Marshfield Clinic IRB approved use of their electronic medical record to search for subjects with at least two serum ALP values ≤40 U/L (normal 40-125 U/L). When the temporal evolution of the qualifying ALP values indicated a precipitous lowering from usually normal serum ALP values, the subject was deemed to have acute hypophosphatasemia. Thirty years of laboratory data and 10 years of clinical narrative were analyzed. Associated diagnoses, clinical circumstances, and short-term mortality were recorded. Results: A total of 458,767 subjects had 2,584,051 serum ALP values, and 5,190 (1.1%) subjects had at least two serum values ≤40 U/L. A detailed review of 1,276 subjects selected on the basis of their lowest ALP value and age identified 190 subjects with acute hypophosphatasemia. Acute hypophosphatasemia was recorded during periods of major trauma/surgery, multisystem failure, acute anemia, blood product transfusions (often massive), apheresis, hypo-magnesemia, and acute caloric restriction. Twenty-eight subjects (15%) died within 35 days of their nadir serum ALP. Conclusion: Acute hypophosphatasemia is associated with profound illness or physiologic stress and followed by increased short-term mortality. The temporal evolution of hypophosphatasemia may relate to its cause. © International Osteoporosis Foundation and National Osteoporosis Foundation 2013.


McKiernan F.E.,Center for Bone Disease | Berg R.L.,Biomedical Informatics Research Center | Fuehrer J.,Biomedical Informatics Research Center
Journal of Bone and Mineral Research | Year: 2014

A serum alkaline phosphatase value below the age-adjusted lower limits of normal (hypophosphatasemia) is uncommonly encountered in clinical practice. The electronic and paper medical records of 885,165 patients treated between 2002 and 2012 at a large, rural, multispecialty health clinic were interrogated to estimate the prevalence and characterize the clinical and radiographic findings of adults whose serum alkaline phosphatase was almost always low (persistent hypophosphatasemia). We hypothesized that some of these patients might harbor previously unrecognized hypophosphatasia, a rare, inherited condition of impaired mineralization of bones and teeth. Persistent hypophosphatasemia (serum alkaline phosphatase ≤30 IU/L) was found in 1 of 1544 adult patients. These adult patients had more crystalline arthritis, orthopedic surgery, chondrocalcinosis, calcific periarthritis, enthesopathy, and diffuse idiopathic skeletal hyperostosis than a general adult patient population. A gender effect was observed. The clinical and radiographic findings of adult patients with persistent hypophosphatasemia resemble those of the adult form of hypophosphatasia. Clinicians should take notice of persistent hypophosphatasemia, consider the diagnosis of hypophosphatasia, and be cautious when considering potent anti-remodeling therapy in these adults. This population warrants further evaluation. © 2014 American Society for Bone and Mineral Research.


McKiernan F.E.,Center for Bone Disease | Berg R.L.,Biomedical Informatics Research Center | Linneman J.G.,Biomedical Informatics Research Center
Osteoporosis International | Year: 2011

Summary: This very large dual X-ray absorptiometry (DXA) cohort confirmed a significant, inverse relationship between bone mineral density (BMD) Z-scores and the presence of secondary causes of osteoporosis but receiver operating characteristic (ROC) curves indicate that Z-score diagnostic thresholds (such as -2.0) discriminate poorly between the presence and absence of secondary causes of osteoporosis. Introduction: BMD Z-score diagnostic thresholds have been proposed to detect secondary causes of osteoporosis. To determine the sensitivity and diagnostic utility of such thresholds, we analyzed comprehensive BMD and personal health information data from a large, multispecialty group practice. Methods: Adult subjects were assigned their lowest axial BMD Z-score and ICD-9 diagnosis codes for secondary causes of osteoporosis when cited at least twice in their electronic medical record. Multiple logistic regression was used to model the prevalence of matching ICD-9 codes as a function of Z-score. ROC curves were used to investigate various Z-score cut points for sensitivity and specificity. Results: Eighteen thousand six hundred seventy-four subjects were analyzed. Secondary causes of osteoporosis were identified in 31% of men and 16% of women. The frequency of secondary causes varied with age and between genders and varied inversely with Z-score. No inflection point was observed in this relationship to suggest a useful clinical decision threshold. The difference in mean Z-score of those with and without a secondary cause of osteoporosis was biologically slight (±0.3). Low Z-score diagnostic thresholds were insensitive to the presence of secondary causes of osteoporosis and provided relatively poor predictive value. Conclusions: This DXA cohort confirmed a significant inverse relationship between Z-score and the presence of secondary causes of osteoporosis but diagnostic Z-score thresholds discriminate poorly between the presence and absence of secondary causes of osteoporosis. If only patients with very low Z-scores are evaluated for secondary causes of osteoporosis the diagnostic specificity may be high but most cases will be missed. © 2010 International Osteoporosis Foundation and National Osteoporosis Foundation.


Duellman T.,University of Wisconsin - Madison | Warren C.L.,Illumavista Biosciences, Llc | Peissig P.,Biomedical Informatics Research Center | Wynn M.,University of Wisconsin - Madison | Yang J.,University of Wisconsin - Madison
Circulation: Cardiovascular Genetics | Year: 2012

Background: Degradation of extracellular matrix support in the large abdominal arteries contribute to abnormal dilation of aorta, leading to abdominal aortic aneurysms, and matrix metalloproteinase-9 (MMP-9) is the predominant enzyme targeting elastin and collagen present in the walls of the abdominal aorta. Previous studies have suggested a potential association between MMP-9 genotype and abdominal aortic aneurysm, but these studies have been limited only to the p-1562 and (CA) dinucleotide repeat microsatellite polymorphisms in the promoter region of the MMP-9 gene. We determined the functional alterations caused by 15 MMP-9 single-nucleotide polymorphisms (SNPs) reported to be relatively abundant in the human genome through Western blots, gelatinase, and promoter-reporter assays and incorporated this information to perform a logistic-regression analysis of MMP-9 SNPs in 336 human abdominal aortic aneurysm cases and controls. Methods and Results: Significant functional alterations were observed for 6 exon SNPs and 4 promoter SNPs. Genotype analysis of frequency-matched (age, sex, history of hypertension, hypercholesterolemia, and smoking) cases and controls revealed significant genetic heterogeneity exceeding 20% observed for 6 SNPs in our population of mostly white subjects from Northern Wisconsin. A step-wise logistic-regression analysis with 6 functional SNPs, where weakly contributing confounds were eliminated using Akaike information criteria, gave a final 2 SNP (D165N and p-2502) model with an overall odds ratio of 2.45 (95% confdence interval, 1.06-5.70). Conclusions: The combined approach of direct experimental confrmation of the functional alterations of MMP-9 SNPs and logistic-regression analysis revealed significant association between MMP-9 genotype and abdominal aortic aneurysm. © 2012 American Heart Association, Inc.


Chute C.G.,Mayo Medical School | Ullman-Cullere M.,Dana-Farber Cancer Institute | Wood G.M.,Clinical Genetics Institute | Lin S.M.,Biomedical Informatics Research Center | And 2 more authors.
Genetics in Medicine | Year: 2013

Health care has become increasingly information intensive. The advent of genomic data, integrated into patient care, significantly accelerates the complexity and amount of clinical data. Translational research in the present day increasingly embraces new biomedical discovery in this data-intensive world, thus entering the domain of "big data." The Electronic Medical Records and Genomics consortium has taught us many lessons, while simultaneously advances in commodity computing methods enable the academic community to affordably manage and process big data. Although great promise can emerge from the adoption of big data methods and philosophy, the heterogeneity and complexity of clinical data, in particular, pose additional challenges for big data inferencing and clinical application. However, the ultimate comparability and consistency of heterogeneous clinical information sources can be enhanced by existing and emerging data standards, which promise to bring order to clinical data chaos. Meaningful Use data standards in particular have already simplified the task of identifying clinical phenotyping patterns in electronic health records. © American College of Medical Genetics and Genomics.


Pieczkiewicz D.S.,Biomedical Informatics Research Center | Finkelstein S.M.,University of Minnesota
Journal of the American Medical Informatics Association | Year: 2010

Clinicians face an increasing volume of biomedical data. Assessing the efficacy of systems that enable accurate and timely clinical decision making merits corresponding attention. This paper discusses the multiple-reader multiple-case (MRMC) experimental design and linear mixed models as means of assessing and comparing decision accuracy and latency (time) for decision tasks in which clinician readers must interpret visual displays of data. These tools can assess and compare decision accuracy and latency (time). These experimental and statistical techniques, used extensively in radiology imaging studies, offer a number of practical and analytic advantages over more traditional quantitative methods such as percent-correct measurements and ANOVAs, and are recommended for their statistical efficiency and generalizability. An example analysis using readily available, free, and commercial statistical software is provided as an appendix. While these techniques are not appropriate for all evaluation questions, they can provide a valuable addition to the evaluative toolkit of medical informatics research.


VanWormer J.J.,Center for Clinical Epidemiology and Population Health | Miller A.W.,Biomedical Informatics Research Center | Rezkalla S.H.,Marshfield Clinic
Clinical Epidemiology | Year: 2014

Background: Aspirin is commonly used for the primary prevention of cardiovascular disease (CVD) in the US. Previous research has observed significant levels of inappropriate aspirin use for primary CVD prevention in some European populations, but the degree to which aspirin is overutilized in the US remains unknown. This study examined the association between regular aspirin use and demographic/clinical factors in a population-based sample of adults without a clinical indication for aspirin for primary prevention.Methods: A cross-sectional analysis was performed using 2010–2012 data from individuals aged 30–79 years in the Marshfield Epidemiologic Study Area (WI, USA). Regular aspirin users included those who took aspirin at least every other day.Results: There were 16,922 individuals who were not clinically indicated for aspirin therapy for primary CVD prevention. Of these, 19% were regular aspirin users. In the final adjusted model, participants who were older, male, lived in northern Wisconsin, had more frequent medical visits, and had greater body mass index had significantly higher odds of regular aspirin use (P<0.001 for all). Race/ethnicity, health insurance, smoking, blood pressure, and lipid levels had negligible influence on aspirin use. A sensitivity analysis found a significant interaction between age and number of medical visits, indicating progressively more aspirin use in older age groups who visited their provider frequently.Conclusion: There was evidence of aspirin overutilization in this US population without CVD. Older age and more frequent provider visits were the strongest predictors of inappropriate aspirin use. Obesity was the only significant clinical factor, suggesting misalignment between perceived aspirin benefits and cardiovascular risks in this subgroup of patients. Prospective studies that examine cardiac and bleeding events associated with regular aspirin use among obese samples (without CVD) are needed to refine clinical guidelines in this area. © 2014 VanWormer et al.


Acharya A.,Biomedical Informatics Research Center
American Journal of Epidemiology | Year: 2013

An oral health surveillance platform that queries a clinical/administrative data warehouse was applied to estimate regional prevalence of periodontitis. Cross-sectional analysis of electronic health record data collected between January 1, 2006, and December 31, 2010, was undertaken in a population sample residing in Ladysmith, Wisconsin. Eligibility criteria included: 1) residence in defined zip codes, 2) age 25-64 years, and 3) ≥1 Marshfield dental clinic comprehensive examination. Prevalence was established using 2 independent methods: 1) via an algorithm that considered clinical attachment loss and probe depth and 2) via standardized Current Dental Terminology (CDT) codes related to periodontal treatment. Prevalence estimates were age-standardized to 2000 US Census estimates. Inclusion criteria were met by 2,056 persons. On the basis of the American Academy of Periodontology/Centers for Disease Control and Prevention method, the age-standardized prevalence of moderate or severe periodontitis (combined) was 407 per 1,000 males and 308 per 1,000 females (348/1,000 males and 269/1,000 females using the CDT code method). Increased prevalence and severity of periodontitis was noted with increasing age. Local prevalence of periodontitis was consistent with national estimates. The need to address potential sample selection bias in future electronic health record-based periodontitis research was identified by this approach. Methods outlined herein may be applied to refine oral health surveillance systems, inform dental epidemiologic methods, and evaluate interventional outcomes. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.


Kalkatawi M.,King Abdullah University of Science and Technology | Rangkuti F.,King Abdullah University of Science and Technology | Schramm M.,King Abdullah University of Science and Technology | Jankovic B.R.,King Abdullah University of Science and Technology | And 4 more authors.
Bioinformatics | Year: 2012

Motivation: Recognition of poly(A) signals in mRNA is relatively straightforward due to the presence of easily recognizable polyadenylic acid tail. However, the task of identifying poly(A) motifs in the primary genomic DNA sequence that correspond to poly(A) signals in mRNA is a far more challenging problem. Recognition of poly(A) signals is important for better gene annotation and understanding of the gene regulation mechanisms. In this work, we present one such poly(A) motif prediction method based on properties of human genomic DNA sequence surrounding a poly(A) motif. These properties include thermodynamic, physico-chemical and statistical characteristics. For predictions, we developed Artificial Neural Network and Random Forest models. These models are trained to recognize 12 most common poly(A) motifs in human DNA. Our predictors are available as a free web-based tool accessible at http://cbrc.kaust.edu.sa/dps. Compared with other reported predictors, our models achieve higher sensitivity and specificity and furthermore provide a consistent level of accuracy for 12 poly(A) motif variants. © The Author(s) 2011. Published by Oxford University Press. All rights reserved.

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