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  • 1. Ahmad, Shafqat
    et al.
    Mora, Samia
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
    Orho-Melander, Marju
    Ridker, Paul M.
    Hu, Frank B.
    Chasman, Daniel I.
    Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 231-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.

    METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.

    RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.

    CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

  • 2. Ahmad, Shafqat
    et al.
    Mora, Samia
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
    Orho-Melander, Marju
    Ridker, Paul M.
    Hu, Frank B.
    Chasman, Daniel I.
    Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 231-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.

    METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.

    RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.

    CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

  • 3. Ahmad, Shafqat
    et al.
    Mora, Samia
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
    Orho-Melander, Marju
    Ridker, Paul M.
    Hu, Frank B.
    Chasman, Daniel I.
    Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 231-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.

    METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.

    RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.

    CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

  • 4.
    Alehagen, Urban
    et al.
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
    Lindstedt, Göran
    Sahlgren Academy at Gothenburg University, Gothenburg, Sweden.
    Eriksson, Henry
    Department of Medicine, Sahlgrenska University Hospital-Östra, Gothenburg, Sweden.
    Dahlström, Ulf
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
    Utility of the amino-terminal fragment of pro-brain natriuretic peptide in plasma for the evaluation of cardiac dysfunction in elderly patients in primary health care2003In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 49, no 8, p. 1337-1346Article in journal (Refereed)
    Abstract [en]

    Background: The aims of this study were to measure the N-terminal fragment of pro-brain natriuretic peptide (proBNP) in plasma in medical conditions commonly found in primary care and to evaluate the utility of these measurements in identifying impaired cardiac function in elderly patients with symptoms associated with heart failure.

    Methods: We studied 415 patients (221 men and 194 women; mean age, 72 years) who had contacted a primary healthcare center for dyspnea, fatigue, and/or peripheral edema. One cardiologist evaluated the patients in terms of history, physical examination, functional capacity, electrocardiography, and suspicion of heart failure. Plasma N-terminal proBNP was measured by an in-house RIA. An ejection fraction ≤40% by Doppler echocardiography was regarded as reduced cardiac function. Abnormal diastolic function was defined as an abnormal mitral inflow defined as reduced ratio of peak early diastolic filling velocity to peak filling velocity at atrial contraction (E/A ratio), or as abnormal pulmonary venous flow pattern.

    Results: Patients with impaired functional capacity, impaired systolic function, and/or impaired renal function had significantly increased N-terminal proBNP concentrations. By multiple regression analysis, N-terminal proBNP concentrations were also influenced by ischemic heart disease, cardiac enlargement, and certain medications but not by increased creatinine. No gender differences were observed. Patients with isolated diastolic dysfunction attributable to relaxation abnormali-ties had lower concentrations than those with normal cardiac function, whereas those with pseudonormal E/A ratios or restrictive filling patterns had higher concentrations.

    Conclusions: Plasma N-terminal proBNP concentrations increase as a result of impaired systolic function, age, impaired renal function, cardiac ischemia and enlargement, and certain medications. Values are high in diastolic dysfunction with pseudonormal patterns, but not in patients with relaxation abnormalities. An increase in plasma N-terminal proBNP might be an earlier sign of abnormal cardiac function than abnormalities identified by currently used echocardiographic measurements.

  • 5. Aomori, Tohru
    et al.
    Yamamoto, Koujirou
    Oguchi-Katayama, Atsuko
    Kawai, Yuki
    Ishidao, Takefumi
    Mitani, Yasumasa
    Kogo, Yasushi
    Lezhava, Alexander
    Fujita, Yukiyoshi
    Obayashi, Kyoko
    Nakamura, Katsunori
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ekström, Lena
    Skogastierna, Cristine
    Rane, Anders
    Kurabayashi, Masahiko
    Murakami, Masami
    Cizdziel, Paul E.
    Hayashizaki, Yoshihide
    Horiuchi, Ryuya
    Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 22009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 4, p. 804-812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h of blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.

  • 6. Baxter, Douglas
    et al.
    Rodushkin, Ilya
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Geosciences and Environmental Engineering.
    Engström, Emma
    Klockare, Dennis
    ALS Analytica AB, Luleå.
    Waara, Hans
    ALS Analytica AB, Luleå.
    Methylmercury measurement in whole blood by isotope-dilution GC-ICPMS with 2 sample preparation methods2007In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 53, no 1, p. 111-116Article in journal (Refereed)
    Abstract [en]

    Background: Despite its known toxicity, methylmercury is rarely measured directly in clinical studies; instead, conclusions are based on total mercury measurements. We have developed isotope-dilution-based methods for methylmercury-specific analysis of whole blood by coupled gas chromatography-inductively coupled plasma mass spectrometry (GC-ICPMS). Methods: We analyzed animal and human blood samples after alkaline digestion or extraction of methylmercury into dichloromethane and back extraction into water. Methylmercury was converted to the volatile ethyl derivative, purged, and trapped on a solid-phase collection medium, and then introduced into the GC-ICPMS system. Results: Limits of quantification were 0.4 and 0.03 mu g/L at a signal-to-noise ratio of 10 with the alkaline digestion and extraction methods, respectively. Extraction met our selected acceptable total error criterion, with an SD of 0.58 mu g/L at the critical maternal blood concentration of 5.8 mu g/L.Results obtained with alkaline digestion indicated the need for improved random analytical uncertainty, which was achieved by increasing the enrichment of the isotope dilution. For 37 blood samples, the mean (SD) proportion of total mercury present as methylmercury was 60 (27)%, range 6%-100%.Conclusions: The combination of extraction and isotope-dilution GC-ICPMS meets the requirements for use as a reference method for measuring methylmercury in whole blood.

  • 7.
    Berg, Cecilia
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Hedrum, A
    Holmberg, A
    Pontén, F
    Uhlén, M
    Lundeberg, J
    Direct solid-phase sequence analysis of the human p53 gene by use of multiplex polymerase chain reaction and alpha-thiotriphosphate nucleotides.1995In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 41, no 10, p. 1461-6Article in journal (Refereed)
    Abstract [en]

    Among the candidate cancer-prognostic genes is the p53 tumor suppressor gene, which, when mutated, plays an important role in the development of many types of cancers. To facilitate robust large-scale DNA analysis of microdissected tumor biopsies, we describe a multiplex/nested PCR approach for a simultaneous outer amplification of exons 4-9 of the human p53 gene with parallel amplification of the HLA-DQB1 locus, involving a total of 14 primers. This approach reduces the required number of cells for analysis and avoids any variation in the amplifications of the individual p53 exons during the common outer amplification step. The HLA sequencing allows sample identification because the DQB1 locus is highly polymorphic and is thereby patient-specific. The p53 and HLA amplicons are analyzed by solid-phase sequencing in a semiautomated format. To improve the DNA sequence quality, we used 2'-deoxyribonucleoside 5'-O-1-thiotriphosphates in the sequencing reactions.

  • 8. Berois, Nora
    et al.
    Blanc, Etienne
    Ripoche, Hugues
    Mergui, Xénia
    Trajtenberg, Felipe
    Cantais, Sabrina
    Barrois, Michel
    Dessen, Philippe
    Kågedal, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Bénard, Jean
    Osinaga, Eduardo
    Raguénez, Gilda
    ppGalNAc-TI3: A new molecular marker of bone marrow involvement in neuroblastoma2006In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 52, no 9, p. 1701-1712Article in journal (Refereed)
    Abstract [en]

    Background: To identify new molecular markers of bone marrow dissemination in human neuroblastoma (NB), we studied the transcriptome profiles of malignant neuroblasts established from the human MYCN-amplified IGR-N-91 model. Methods: This experimental model includes human neuroblastoma cells derived from & subcutaneous stage 4 disease, myocardium (Myoc) and bone marrow (BM) metastatic cells. Results: Gene expression profiles obtained with Agilent oligo microarrays revealed a set of 107 differentially expressed genes in the metastatic neuroblasts. This set included up-regulated genes involved in chemoresistance, cell motility, neuronal structure/signaling, and the recently characterized GALNT13 gene encoding a glycosyltransferase that initiates mucin-type O-glycosylation. Because the glycosylation process is involved in the progression of primary tumor to metastatic disease, we investigated whether the most strongly upregulated gene, GALNT13, might be a marker of bone marrow involvement in stage 4 NB patients. Importantly, in the BM of healthy adults no GALNT13 transcript was detected with analysis by quantitative (n = 3) and nested reverse transcription-PCR (n = 4) assays. In contrast, GALNT13 transcripts were detected in 23/23 cytologically involved BM samples obtained at diagnosis of stage 4 NB patients and in 5/27 cytologically noninvolved BM samples obtained from patients with stage 1-4 and 4S and treated stage 4 NB. The quantitative measurements of tyrosine hydroxylase (TH), ganglioside D2 synthase, dopa decarboxylase, and GALNT13 transcript values were compared in the same NB patients, and the results showed that GALNT13 expression was most highly correlated to poor clinical outcome at diagnosis. Conclusion: We propose ppGalNAc-T13 as a new informative marker for the molecular diagnosis of BM involvement and the follow-up of minimal residual disease in NB patients. © 2006 American Association for Clinical Chemistry.

  • 9.
    Breimer, Lars H.
    et al.
    Fac Med & Hlth, Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Torbjorn K.
    Dept Med Biosci, Clin Chem, Umeå Univ, Umeå, Sweden.
    Is Ferrotoxicity a New Great Public Health Challenge?2015In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 61, no 4, p. 667-668Article in journal (Refereed)
  • 10. Breimer, Lars H
    et al.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Is ferrotoxicity a new great public health challenge?2015In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 61, no 4, p. 667-668Article in journal (Refereed)
  • 11. Ceder, Gunnel
    et al.
    Jones, A Wayne
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry.
    Concentration ratios of morphine to codeine in blood of impaired drivers as evidence of heroin use and not medication with codeine2001In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 47, no 11, p. 1980-1984Article in journal (Refereed)
    Abstract [en]

    Background: Both the illicit drug heroin and the prescription drug codeine are metabolized to morphine, which tends to complicate interpretation of opiate-positive samples. We report here the concentrations of morphine and codeine, the morphine/codeine ratios, and 6-acetylmorphine (6-AM) in blood specimens from individuals arrested for driving under the influence of drugs (DUID) in Sweden. The results were compared with positive findings of 6-AM in urine as evidence of heroin intake. Methods: In 339 DUID suspects, both blood and urine specimens were available for toxicologic analysis. In another 882 cases, only blood was available. All specimens were initially analyzed by immunoassay, and the positive results were verified by isotope-dilution gas chromatography-mass spectrometry. In routine casework, the limits of quantification (LOQs) for unconjugated opiates were 5 ng/g for blood and 20 ╡g/L for urine. Results: The median concentration of morphine in blood was 30 ng/g with 2.5 and 97.5 percentiles of 5 and 230 ng/g, respectively (n = 979). This compares with a median codeine concentration of 20 ng/g and 2.5 and 97.5 percentiles of 5 and 592 ng/g, respectively (n = 784). The specific metabolite of heroin, 6-AM, was identified in only 16 of 675 blood specimens (2.3%). This compares with positive findings of 6-AM in 212 of 339 urine samples (62%) from the same population of DUID suspects. When 6-AM was identified in urine, the morphine/codeine ratio in blood was always greater than unity (median, 6.0, range, 1-66). In 18 instances, 6-AM was present in urine, although morphine and codeine were below the LOQ in blood. The morphine/codeine ratio in blood was greater than unity in 85% of DUID cases when urine was not available (n = 506), and the median morphine and codeine concentrations were 70 ng/g and 10 ng/g, respectively. When morphine/codeine ratios in blood were less than unity (n = 76), the median morphine and codeine concentrations were 10 ng/g and 180 ng/g, respectively. Conclusions: Only 2.3% of opiate-positive DUID suspects were verified as heroin users on the basis of positive findings of 6-AM in blood. A much higher proportion (62%) were verified heroin users from 6-AM identified in urine. When urine was not available for analysis, finding a morphine/codeine concentration ratio in blood above unity suggests heroin use and not medication with codeine. This biomarker indicated that 85% of opiate-positive DUID blood samples were from heroin users. ⌐ 2001 American Association for Clinical Chemistry.

  • 12.
    Chinnasamy, Thiruppathiraja
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Segerink, Loes I.
    Nystrand, Mats
    Gantelius, Jesper
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Point-of-Care Vertical Flow Allergen Microarray Assay: Proof of Concept2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 9, p. 1209-1216Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sophisticated equipment, lengthy protocols, and skilled operators are required to perform protein microarray-based affinity assays. Consequently, novel tools are needed to bring biomarkers and biomarker panels into clinical use in different settings. Here, we describe a novel paper-based vertical flow microarray (VFM) system with a multiplexing capacity of at least 1480 microspot binding sites, colorimetric readout, high sensitivity, and assay time of < 10 min before imaging and data analysis. METHOD: Affinity binders were deposited on nitrocellulose membranes by conventional microarray printing. Buffers and reagents were applied vertically by use of a flow controlled syringe pump. As a clinical model system, we analyzed 31 precharacterized human serum samples using the array system with 10 allergen components to detect specific IgE reactivities. We detected bound analytes using gold nanoparticle conjugates with assay time of <= 10 min. Microarray images were captured by a consumer-grade flatbed scanner. RESULTS: A sensitivity of 1 ng/mL was demonstrated with the VFM assay with colorimetric readout. The reproducibility (CV) of the system was < 14%. The observed concordance with a clinical assay, Immuno-CAP, was R-2 = 0.89 (n = 31). CONCLUSIONS: In this proof-of-concept study, we demonstrated that the VFM assay, which combines features from protein microarrays and paper-based colorimetric systems, could offer an interesting alternative for future highly multiplexed affinity point-of-care testing.

  • 13. Clarke, Robert
    et al.
    Sherliker, Paul
    Hin, Harold
    Nexo, Ebba
    Hvas, Anne Mette
    Schneede, Joern
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Birks, Jacqueline
    Ueland, Per M
    Emmens, Kathleen
    Scott, John M
    Molloy, Anne M
    Evans, John Grimley
    Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin.2007In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 53, no 5, p. 963-970Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Impaired vitamin B(12) function and decreased vitamin B(12) status have been associated with neurological and cognitive impairment. Current assays analyze total vitamin B(12) concentration, only a small percentage of which is metabolically active. Concentrations of this active component, carried on holotranscobalamin (holoTC), may be of greater relevance than total vitamin B(12). METHODS: We compared the utility of serum holoTC with conventional vitamin B(12) for detection of vitamin B(12) deficiency in a population-based study of older people, using increased methylmalonic acid (MMA) concentrations as a marker of metabolic vitamin B(12) deficiency in the overall population (n = 2403) and in subsets with normal (n = 1651) and abnormal (n = 752) renal function. RESULTS: Among all participants, 6% had definite (MMA >0.75 micromol/L) and 16% had probable (MMA >0.45 micromol/L) metabolic vitamin B(12) deficiency. In receiver operating characteristic curves for detection of definite vitamin B(12) deficiency, holoTC had a greater area under the curve (AUC) compared with vitamin B(12) in all participants (0.85 vs 0.76; P <0.001) and in subsets with normal (AUC: 0.87 vs 0.79; P <0.001) and abnormal (AUC: 0.85 vs 0.74; P = 0.002) renal function. Similar findings were observed for detection of moderate vitamin B(12) deficiency. Whereas the positive predictive value for both holoTC and vitamin B(12) was greater for detection of probable than definite vitamin B(12) deficiency, both tests were associated with more false-positive than true-positive test results. CONCLUSIONS: HoloTC has a modestly superior diagnostic accuracy compared with conventional vitamin B(12) for the detection of vitamin B(12) deficiency, but neither test can be recommended to screen asymptomatic populations.

  • 14.
    Darmanis, Spyros
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Gallant, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    PCR-Based Multiparametric Assays in Single Cells.2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 12, p. 1618-1619Article in journal (Refereed)
  • 15.
    Dizdar (Dizdar Segrell), Nil
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences.
    Kullman, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Norlander, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Olsson, Jan-Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Human pharmacokinetics of L-3,4-dihydroxyphenylalanine studied with microdialysis1999In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 45, no 10, p. 1813-1820Article in journal (Refereed)
    Abstract [en]

    Background: Intravenous and subcutaneous microdialysis was performedto compare the free concentrations and pharmacokinetics of L-3,4-dihyroxyphenylalanine(L-dopa) in blood and tissue in healthy subjects and in patientswith Parkinson disease.

    Methods: Nine healthy volunteers and 10 patients with Parkinson disease, stage 1.5–2 according to the Hoehn-Yahr rating scale, took part of the study. In the patient group subcutaneous microdialysis and ordinary blood sampling were performed, whereas in the control group intravenous microdialysis was also performed. Microdialysis samples were collected in fractions of 15 min. The first two fractions were collected for analysis of basal concentrations. A blood sample was also taken. The patients were then given one tablet of Madopar® (100 mg of L-dopa and 25 mg of benserazide),and the microdialysis was continued for another 210 min. Bloodsamples were obtained at 30-min intervals.

    Results: The serum samples gave a significantly higher meanarea under the curve (AUC; 491 ± 139 µmol ·min/L) than that for intravenous dialysates (235 ± 55.3µmol · min/L), suggesting a protein binding of50%. The L-dopa concentrations from the subcutaneous dialysatesmatched those from the intravenous dialysates, indicating rapiddistribution of L-dopa to the tissues.

    Conclusions: Parkinsonian patients in early stages of the disease have a pharmacokinetic pattern of free L-dopa similar to that of healthy subjects. Comparison of AUCs from microdialysis with ordinary serum analysis revealed data indicating significant protein binding. Microdialysis is a suitable and easily applied tool in pharmacokinetic studies.

  • 16. DOrazio, Paul
    et al.
    Burnett, Robert W
    Fogh-Andersen, Niels
    Jacobs, Ellis
    Kuwa, Katsuhiko
    Külpmann, Wolf R
    Larsson, Lasse
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Lewenstam, Andrzej
    Maas, Anton H J
    Mager, Gerhard
    Naskalski, Jerzy W
    Okorodudu, Anthony O
    Approved IFCC recommendation on reporting results for blood glucose (abbreviated)2005In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 51, no 9, p. 1573-1576Article in journal (Refereed)
    Abstract [en]

    In current clinical practice, plasma and blood glucose are used interchangeably with a consequent risk of clinical misinterpretation. In human blood, glucose, like water, is distributed between erythrocytes and plasma. The molality of glucose (amount of glucose per unit of water mass) is the same throughout the sample, but the concentration is higher in plasma because the concentration of water and, therefore, glucose is higher in plasma than in erythrocytes. Different devices for the measurement of glucose may detect and report fundamentally different quantities. Different water concentrations in calibrators, plasma, and erythrocyte fluid can explain some of the differences. Results of glucose measurements depend on sample type and on whether methods require sample dilution or use biosensors in undiluted samples. If the results are mixed up or used indiscriminately, the differences may exceed the maximum allowable error of glucose determinations for diagnosing and monitoring diabetes mellitus, and complicate the treatment. The goal of the IFCC Scientific Division Working Group on Selective Electrodes and Point of Care Testing (IFCC-SD, WG-SEPOCT) is to reach a global consensus on reporting results. The document recommends reporting the concentration of glucose in plasma (with the unit mmol/L), irrespective of sample type or measurement technique. A constant factor of 1.11 is used to convert concentration in whole blood to the equivalent concentration in the pertinent plasma. The conversion will provide harmonized results, facilitating the classification and care of patients and leading to fewer therapeutic misjudgments. © 2005 American Association for Clinical Chemistry.

  • 17. Drogan, Dagmar
    et al.
    Dunn, Warwick B.
    Lin, Wanchang
    Buijsse, Brian
    Schulze, Matthias B.
    Langenberg, Claudia
    Brown, Marie
    Floegel, Anna
    Dietrich, Stefan
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wedge, David C.
    Goodacre, Royston
    Forouhi, Nita G.
    Sharp, Stephen J.
    Spranger, Joachim
    Wareham, Nick J.
    Boeing, Heiner
    Untargeted Metabolic Profiling Identifies Altered Serum Metabolites of Type 2 Diabetes Mellitus in a Prospective, Nested Case Control Study2015In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 61, no 3, p. 487-497Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Application of metabolite profiling could expand the etiological knowledge of type 2 diabetes mellitus (T2D). However, few prospective studies apply broad untargeted metabolite profiling to reveal the comprehensive metabolic alterations preceding the onset of T2D. METHODS: We applied untargeted metabolite profiling in serum samples obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 300 individuals who developed T2D after a median follow-up time of 6 years and 300 matched controls. For that purpose, we used ultraperformance LC-MS with a protocol specifically designed for large-scale metabolomics studies with regard to robustness and repeatability. After multivariate classification to select metabolites with the strongest contribution to disease classification, we applied multivariable-adjusted conditional logistic regression to assess the association of these metabolites with T2D.

    RESULTS: Among several alterations in lipid metabolism, there was an inverse association with T2D for metabolites chemically annotated as lysophosphatidylcholine(dm16:0) and phosphatidylcholine(O-20:0/O-20:0). Hexose sugars were positively associated with T2D, whereas higher concentrations of a sugar alcohol and a deoxyhexose sugar reduced the odds of diabetes by approximately 60% and 70%, respectively. Furthermore, there was suggestive evidence for a positive association of the circulating purine nucleotide isopentenyladenosine-5' -monophosphate with incident T2D.

    CONCLUSIONS: This study constitutes one of the largest metabolite profiling approaches of T2D biomarkers in a prospective study population. The findings might help generate new hypotheses about diabetes etiology and develop further targeted studies of a smaller number of potentially important metabolites. (C) 2014 American Association for Clinical Chemistry

  • 18.
    Ebai, T
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marques Souza de Oliviera, F
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löf, L
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schweiger, C
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Keilholtz, U
    Haybaeck, J
    Kamali-Moghaddam, M
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sensitive protein detection by proximity ligation withrolling circle amplification in microtiter plates.2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561Article in journal (Refereed)
  • 19.
    Ebai, Tonge
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    de Oliveira, Felipe Marques Souza
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Löf, Liza
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Wik, Lotta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Schweiger, Caroline
    Charité Comprehensive Cancer Center, University of Berlin, Berlin, Germany; Institute of Pathology, Medical University of Graz, Graz, Austria; .
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Keilholtz, Ulrich
    Institute of Pathology, Medical University of Graz, Graz, Austria; .
    Haybaeck, Johannes
    Charité Comprehensive Cancer Center, University of Berlin, Berlin, Germany; Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany..
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Analytically Sensitive Protein Detection in Microtiter Plates by Proximity Ligation with Rolling Circle Amplification2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 9, p. 1497-1505Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Detecting proteins at low concentrations in plasma is crucial for early diagnosis. Current techniques in clinical routine, such as sandwich ELISA, provide sensitive protein detection because of a dependence on target recognition by pairs of antibodies, but detection of still lower protein concentrations is often called for. Proximity ligation assay with rolling circle amplification (PLARCA) is a modified proximity ligation assay (PLA) for analytically specific and sensitive protein detection via binding of target proteins by 3 antibodies, and signal amplification via rolling circle amplification (RCA) in microtiter wells, easily adapted to instrumentation in use in hospitals.

    METHODS: Proteins captured by immobilized antibodies were detected using a pair of oligonucleotide-conjugated antibodies. Upon target recognition, these PLA probes guided oligonucleotide ligation, followed by amplification via RCA of circular DNA strands that formed in the reaction. The RCA products were detected by horseradish peroxidase-labeled oligonucleotides to generate colorimetric reaction products with readout in an absorbance microplate reader.

    RESULTS: We compared detection of interleukin (IL)-4, IL-6, IL-8, p53, and growth differentiation factor-15 by PLARCA and conventional sandwich ELISA or immuno RCA. PLARCA detected lower concentrations of proteins and exhibited a broader dynamic range compared ELISA and iRCA using the same antibodies. IL-4 and IL-6 were detected in clinical samples at femtomolar concentrations, considerably lower than for ELISA.

    CONCLUSIONS: PLARCA offers detection of lower protein levels and increased dynamic ranges compared to ELISA. The PLARCA procedure may be adapted to routine instrumentation available in hospitals and research laboratories.

  • 20.
    Ebeling Barbier, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Themudo, Raquel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bjerner, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Cardiac Troponin I Associated with the Development of Unrecognized Myocardial Infarctions Detected with MRI2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 10, p. 1327-1335Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Late enhancement MRI (LE-MRI) and cardiac troponin I (cTnI) are sensitive methods to detect subclinical myocardial injury. We sought to investigate the relation between plasma concentrations of cTnI measured with a high-sensitivity assay (hs-cTnI) and the development of unrecognized myocardial infarctions (UMIs) detected with LE-MRI.

    METHODS:

    After approval from the ethics committee and written informed consent were obtained, LE-MRI was performed on 248 randomly selected community-living 70-year-old volunteers and hs-cTnI was determined with a highly sensitive premarket assay. Five years later these individuals were invited to a second LE-MRI, and 176 of them (82 women, 94 men), who did not have a hospital diagnosis of MI, constitute the present study population. LE-MR images were analyzed by 2 radiologists independently and in a consensus reading, blinded to any information on previous disease or assessments.

    RESULTS:

    New or larger UMIs were detected in 37 participants during follow-up. Plasma concentrations of hs-cTnI at 70 years of age, which were mainly within what is considered to be the reference interval, were related to new or larger UMIs at 75 years of age with an odds ratio of 1.98 per 1 unit increase in ln-transformed cTnI (95% CI, 1.17-3.35; P = 0.010). Plasma concentrations of hs-cTnI at 70 years of age were associated with the volumes of the UMIs detected at 75 years of age (P = 0.028).

    CONCLUSIONS:

    hs-cTnI in 70-year-old community-living women and men was associated with the development of MRI-detected UMIs within 5 years.

  • 21.
    Eggers, Kai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Impact of sex on cardiac troponin concentrations – A critical appraisal.2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 9, p. 1457-1464Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND:

    The use of sex-specific cutoffs for cardiac troponin (cTn) is currently debated. Although endorsed by scientific working groups, concerns have been raised that sex-specific cutoffs may have only a small clinical effect at the cost of increased complexity in decision-making.

    METHODS:

    We reviewed studies investigating the interrelations between high-sensitivity (hs) cTn results and sex, diagnoses, and outcome. Investigated populations included community-dwelling subjects and patients with stable angina, congestive heart failure, or acute chest pain including those with acute coronary syndromes.

    RESULTS:

    Men usually have higher hs-cTn concentrations compared with women, regardless of the assessed population or the applied assay. The distribution and prognostic implications of hs-cTn concentrations indicate that women have a broader cardiovascular risk panorama compared with men, particularly at lower hs-cTn concentrations. At higher concentrations, particularly above the 99th percentile, this variation is often attenuated. Sex-specific hs-cTn 99th percentiles have so far shown clinical net benefit in only 1 study assessing patients with chest pain. However, several methodological aspects need to be considered when interpreting study results, e.g., issues related to the determination of the 99th percentiles, the selection bias, and the lack of prospective and sufficiently powered analyses.

    CONCLUSIONS:

    Available studies do not show a consistent clinical superiority of sex-specific hs-cTn 99th percentiles. This may reflect methodological aspects. However, from a pathobiological perspective, the use of sex-specific hs-cTn 99th percentiles makes sense for the ruling in of myocardial infarction. We propose a new approach to hs-cTn 99th cutoffs taking into account the analytical properties of the used assays.

  • 22.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Serial Measurement of Biomarkers after Acute Coronary Syndrome: Which One to Choose?2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 7, p. 1181-1183Article in journal (Other academic)
  • 23.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jaffe, Allan S.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Value of cardiac troponin I cutoff concentrations below the 99th percentile for clinical decision-making2009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 1, p. 85-92Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to evaluate factors influencing the 99th percentile for cardiac troponin I (cTnI) when this cutoff value is established on a highly sensitive assay, and to compare the value of this cutoff to that of lower cutoffs in the prognostic assessment of patients with coronary artery disease. METHODS: We used the recently refined Access AccuTnI assay (Beckman-Coulter) to assess the distribution of cTnI results in a community population of elderly individuals [PIVUS (Prospective Study of the Vasculature in Uppsala Seniors) study; n = 1005]. The utility of predefined cTnI cutoffs for risk stratification was then evaluated in 952 patients from the FRISC II (FRagmin and Fast Revascularization during InStability in Coronary artery disease) study at 6 months after these patients had suffered acute coronary syndrome. RESULTS: Selection of assay results from a subcohort of PIVUS participants without cardiovascular disease resulted in a decrease of the 99th percentile from 0.044 microg/L to 0.028 microg/L. Men had higher rates of cTnI elevation with respect to the tested thresholds. Whereas the 99th percentile cutoff was not found to be a useful prognostic indicator for 5-year mortality, both the 90th percentile (hazard ratio 3.1; 95% CI 1.9-5.1) and the 75th percentile (hazard ratio 2.8; 95% CI 1.7-4.7) provided useful prognostic information. Sex-specific cutoffs did not improve risk prediction. CONCLUSIONS: The 99th percentile of cTnI depends highly on the characteristics of the reference population from which it is determined. This dependence on the reference population may affect the appropriateness of clinical conclusions based on this threshold. However, cTnI cutoffs below the 99th percentile seem to provide better prognostic discrimination in stabilized acute coronary syndrome patients and therefore may be preferable for risk stratification.

  • 24.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jernberg, Tomas
    Ljung, Lina
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    High-Sensitivity Cardiac Troponin-Based Strategies for the Assessment of Chest Pain Patients: A Review of Validation and Clinical Implementation Studies2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 11, p. 1572-1585Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: The introduction of high-sensitivity cardiac troponin (hs-cTn) assays has improved the early assessment of chest pain patients. A number of hs-cTn-based algorithms and accelerated diagnostic protocols (ADPs) have been developed and tested subsequently. In this review, we summarize the data on the performance and clinical utility of these strategies. CONTENT: We reviewed studies investigating the diagnostic and prognostic performance of hs-cTn algorithms [level of detection (LoD) strategy, 0/1-h, 0/2-h, and 0/3-h algorithms) and of hs-cTn-based ADPs, together with the implications of these strategies when implemented as clinical routine. The LoD strategy, when combined with a nonischemic electrocardiogram, is best suited for safe rule-out of myocardial infarction and the identification of patients eligible for early discharge from the emergency department. The 0/1-h algorithms appear to identify most patients as being eligible for rule-out. The hs-cTn-based ADPs mainly focus on prognostic assessment, which is in contrast with the hs-cTn algorithms. They identify smaller proportions of rule-out patients, but there is increasing evidence from prospective studies on their successful clinical implementation. Such information is currently lacking for hs-cTn algorithms. CONCLUSIONS: There is a trade-off between safety and efficacy for different hs-cTn-based strategies. This trade-off should be considered for the intended strategy, along with its user-friendliness and evidence from clinical implementation studies. However, several gaps in knowledge remain. At present, we suggest the use of an ADP in conjunction with serial hs-cTn results to optimize the early assessment of chest pain patients. (C) 2018 American Association for Clinical Chemistry

  • 25.
    Eggers, Kai M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kempf, Tibor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wollert, Kai C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community2016In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 62, no 3, p. 485-493Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is increasing interest in measurements of cardiovascular (CV) biomarker concentrations for risk prediction in the general population. We investigated the prognostic utility of a panel of novel CV biomarkers and their changes over time.

    METHODS: We measured concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional proadrenomedullin, high-sensitivity cardiac troponin I, growth-differentiation factor-15 (GDF-15), soluble ST2 (sST2), and galectin-3 at baseline and 5 years later in 1016 elderly individuals participating in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Assessed outcomes included all-cause mortality and fatal and nonfatal CV events (in participants without CV disease at baseline) during 10 years of follow-up.

    RESULTS: GDF-15 exhibited the strongest association with all-cause mortality (n = 158) with a hazard ratio (HR) per 1-SD increase in standardized ln GDF-15 of 1.68 (95% CI, 1.44-1.96). NT-proBNP was the only biomarker to predict CV events (n = 163; HR 1.54 [95% CI, 1.30-1.84]). GDF-15 and NT-proBNP also improved metrics of discrimination and reclassification of the respective outcomes. Changes in GDF-15 concentrations between 70 and 75 years predicted all-cause mortality whereas changes in NT-proBNP predicted both outcomes. The other biomarkers and their temporal changes provided only moderate prognostic value apart from sST2 which had a neutral relationship with adverse events.

    CONCLUSIONS: Evaluation of temporal changes in GDF-15 and NT-proBNP concentrations improves risk prediction in an elderly population. These findings are of considerable interest given the emphasis on biomarkers as tools to identify and monitor at-risk individuals with preclinical and potentially modifiable stages of CV disease.

  • 26.
    Eggers, Kai M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kempf, Tibor
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wollert, Kai C
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Change in Growth Differentiation Factor 15 Concentrations Over Time Independently Predicts Mortality in Community-Dwelling Elderly Individuals2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 7, p. 1091-1098Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Growth differentiation factor 15 (GDF-15) is emerging as a powerful risk indicator in both cardiovascular disease patients and community-dwelling individuals. We investigated GDF-15 concentrations and their changes over 5 years in elderly individuals from the community, together with the underlying conditions and prognostic implications of these measurements.

    METHODS:

    We analyzed GDF-15 concentrations using a sandwich immunoassay in participants from the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. Measurements were performed at both 70 (n = 1004) and 75 (n = 813) years of age. Median follow-up was 8.0 years.

    RESULTS:

    Over time, GDF-15 concentrations increased by 11.0% (P < 0.001). These changes were related to male sex, hypertension, diabetes, heart failure, renal function, and concentrations of N-terminal pro–B-type natriuretic peptide (NT-proBNP). Significant relationships also emerged between changes in GDF-15 and NT-proBNP, C-reactive protein, and renal function between ages 70 and 75. The R2 value of this model was 0.20. GDF-15 concentrations independently predicted all-cause mortality [hazard ratio 4.0 (95% CI 2.7–6.0)] with results obtained at ages 70 and 75 as updated covariates. Baseline GDF-15 concentrations improved prognostic discrimination and reclassification [c-statistic 0.06 (P = 0.006); integrated discrimination improvement = 0.030 (P = 0.004); category-free net reclassification improvement = 0.281 (P = 0.006)]. Change in GDF-15 concentrations over time independently predicted even all-cause mortality occurring after age 75 [hazard ratio 3.6 (95% CI 2.2–6.0)].

    CONCLUSIONS:

    GDF-15 concentrations and their changes over time are powerful predictors of mortality in elderly community-dwelling individuals. GDF-15 concentrations increase with aging, and these changes are explained only partially by cardiovascular risk factors, indicators of neurohumoral activation and inflammation, and renal function. Thus GDF-15 reflects both cardiovascular and other biological processes closely related to longevity.

  • 27.
    Eggers, Kai M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Factors Influencing the 99th Percentile of Cardiac Troponin I Evaluated in Community-Dwelling Individuals at 70 and 75 Years of Age2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 7, p. 1068-1073Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    We aimed to investigate the effects of sex, prevalent cardiovascular disease (CVD), and ageing on the 99th percentile of cardiac troponin I (cTnI).

    METHODS:

    cTnI was measured using a high-sensitivity assay (Abbott Diagnostics) in 814 community-dwelling individuals at both 70 and 75 years of age. We determined the cTnI 99th percentiles separately using nonparametric methods in the total sample, in men and women, and in individuals with and without CVD.

    RESULTS:

    The cTnI 99th percentile at baseline was 55.2 ng/L for the total cohort. Higher 99th percentiles were noted in men (69.3 ng/L) and individuals with CVD (74.5 ng/L). The cTnI 99th percentile in individuals free from CVD at baseline (n = 498) increased by 51% from 38.4 to 58.0 ng/L during the 5-year observation period. Relative increases ranging from 44% to 83% were noted across all subgroups. Male sex [odds ratio, 5.3 (95% CI, 1.5-18.3)], log-transformed N-terminal pro-B-type natriuretic peptide [odds ratio, 1.9 (95% CI, 1.2-3.0)], and left-ventricular mass index [odds ratio, 1.3 (95% CI, 1.1-1.5)] predicted increases in cTnI concentrations from below the 99th percentile (i.e., 38.4 ng/L) at baseline to concentrations above the 99th percentile at the age of 75 years.

    CONCLUSIONS:

    cTnI concentration and its 99th percentile threshold depend strongly on the characteristics of the population being assessed. Among elderly community dwellers, higher concentrations were seen in men and individuals with prevalent CVD. Ageing contributes to increasing concentrations, given the pronounced changes seen with increasing age across all subgroups. These findings should be taken into consideration when applying cTnI decision thresholds in clinical settings.

  • 28.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Application of Cardiac Troponin in Cardiovascular Diseases Other Than Acute Coronary Syndrome2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 1, p. 223-235Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Increased cardiac troponin concentrations in acute coronary syndrome (ACS) identify patients with ongoing cardiomyocyte necrosis who are at increased risk. However, with the use of more precise assays, cardiac troponin increases are commonly noted in other cardiovascular conditions as well. This has generated interest in the use of cardiac troponin for prognostic assessment and clinical management of these patients. In this review, we have summarized the data from studies investigating the implications of cardiac troponin concentrations in various acute and chronic conditions beyond ACS,, i.e., heart failure, myocarditis, Takotsubo cardiomyopathy, aortic dissection, supraventricular arrhythmias, valve disease, pulmonary arterial hypertension, stroke, and in the perioperative setting. CONTENT: Cardiac troponin concentrations are often detectable and frankly increased in non-ACS conditions, in particular when measured with high-sensitivity (hs) assays. With the exception of myocarditis and Takotsubo cardiomyopathy, cardiac troponin concentrations carry strong prognostic information, mainly with respect to mortality, or incipient and/or worsening heart failure. Studies investigating the prognostic benefit associated with cardiac troponin guided treatments however, are almost lacking and the potential role of cardiac troponin in the management of non-ACS conditions is not defined. SUMMARY: Increased cardiac troponin indicates increased risk for adverse outcome in patients with various cardiovascular conditions beyond ACS. Routine measurement of cardiac troponin concentrations can however, not be generally recommended unless there is a suspicion of ACS. Nonetheless, any finding of an increased cardiac troponin concentration in a patient without ACS should at least prompt the search for possible underlying conditions and these should be managed meticulously according to current guidelines to improve outcome.

  • 29.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Impact of Sex on Cardiac Troponin Concentrations: A Critical Appraisal2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 9, p. 1457-1464Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: The use of sex-specific cutoffs for cardiac troponin (cTn) is currently debated. Although endorsed by scientific working groups, concerns have been raised that sex-specific cutoffs may have only a small clinical effect at the cost of increased complexity in decision-making.

    METHODS: We reviewed studies investigating the interrelations between high-sensitivity (hs) cTn results and sex, diagnoses, and outcome. Investigated populations included community-dwelling subjects and patients with stable angina, congestive heart failure, or acute chest pain including those with acute coronary syndromes.

    RESULTS: Men usually have higher hs-cTn concentrations compared with women, regardless of the assessed population or the applied assay. The distribution and prognostic implications of hs-cTn concentrations indicate that women have a broader cardiovascular risk panorama compared with men, particularly at lower hs-cTn concentrations. At higher concentrations, particularly above the 99th percentile, this variation is often attenuated. Sex-specific hs-cTn 99th percentiles have so far shown clinical net benefit in only 1 study assessing patients with chest pain. However, several methodological aspects need to be considered when interpreting study results, e.g., issues related to the determination of the 99th percentiles, the selection bias, and the lack of prospective and sufficiently powered analyses.

    CONCLUSIONS: Available studies do not show a consistent clinical superiority of sex-specific hs-cTn 99th percentiles. This may reflect methodological aspects. However, from a pathobiological perspective, the use of sex-specific hs-cTn 99th percentiles makes sense for the ruling in of myocardial infarction. We propose a new approach to hs-cTn 99th cutoffs taking into account the analytical properties of the used assays.

  • 30.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Carrero, Juan J.
    Karolinska Inst, Div Renal Med, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Evans, Marie
    Karolinska Inst, Div Renal Med, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Szummer, Karolina
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Jernberg, Tomas
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Cardiac Troponins and Their Prognostic Importance in Patients with Suspected Acute Coronary Syndrome and Renal Dysfunction2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 8, p. 1409-1417Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cardiac troponin (cTn) is important for risk assessment in patients with suspected acute coronary syndrome (ACS). cTn concentrations may, however, be affected by renal dysfunction, and the clinical importance of this interrelation is not well established. We investigated the association between cTnT and cTnI (measured with conventional assays and a more sensitive assay) with the estimated glomerular filtration rate (eGFR) and also assessed the ability of cTn to predict the 1-year all-cause mortality. METHODS: This retrospective registry-based study used data from 309454 admissions to Swedish coronary care units. cTn associations with eGFR and mortality were assessed using different regression models and by calculating multivariable-adjusted c-statistics. RESULTS: cTnT concentrations exhibited stronger associations with eGFR than cTnI concentrations (conventional cTnT assay: beta = -0.113; more sensitive cTnT assay: beta = -0.186; pooled conventional cTnI assays: beta = -0.098). Overall, cTnT provided greater prognostic accuracy than cTnI. This was most evident in non-ACS patients with normal or mildly reduced eGFR when using the more sensitive assay. Despite higher mortality rates, no consistent increases in the c-statistics of cTn were seen with severely reduced eGFR irrespective of the presence of ACS or non-ACS. CONCLUSIONS: cTnT concentrations exhibited stronger associations with reduced eGFR than cTnI concentrations in patients admitted because of suspected ACS. cTnT, particularly when measured using the more sensitive assay, also tended to be a stronger prognosticator. However, the relative significance of the obtained results must be considered in the context of the severity of renal dysfunction and whether ACS is present.

  • 31. El-Heliebi, Amin
    et al.
    Hille, Claudia
    Laxman, Navya
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Svedlund, Jessica
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Haudum, Christoph
    Ercan, Erkan
    Kroneis, Thomas
    Chen, Shukun
    Smolle, Maria
    Rossmann, Christopher
    Krzywkowski, Tomasz
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ahlford, Annika
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Devyser AB, Sweden.
    Darai, Evangelia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    von Amsberg, Gunhild
    Alsdorf, Winfried
    König, Frank
    Löhr, Matthias
    de Kruijff, Inge
    Riethdorf, Sabine
    Gorges, Tobias M.
    Pantel, Klaus
    Bauernhofer, Thomas
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sedlmayr, Peter
    In Situ Detection and Quantification of AR-V7, AR-FL, PSA, and KRAS Point Mutations in Circulating Tumor Cells2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 3, p. 536-546Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Liquid biopsies can be used in castration-resistant prostate cancer (CRPC) to detect androgen receptor splice variant 7 (AR-V7), a splicing product of the androgen receptor. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane chemotherapy compared with novel hormonal therapies, indicating a treatment-selection biomarker. Likewise, in those with pancreatic cancer (PaCa), KRAS mutations act as prognostic biomarkers. Thus, there is an urgent need for technology investigating the expression and mutation status of CTCs. Here, we report an approach that adds AR-V7 or KRAS status to CTC enumeration, compatible with multiple CTC-isolation platforms.

    METHODS: We studied 3 independent CTC-isolation devices (CellCollector, Parsortix, CellSearch) for the evaluation of AR-V7 or KRAS status of CTCs with in situ padlock probe technology. Padlock probes allow highly specific detection and visualization of transcripts on a cellular level. We applied padlock probes for detecting AR-V7, androgen receptor full length (AR-FL), and prostate-specific antigen (PSA) in CRPC and KRAS wildtype (wt) and mutant (mut) transcripts in PaCa in CTCs from 46 patients.

    RESULTS: In situ analysis showed that 71% (22 of 31) of CRPC patients had detectable AR-V7 expression ranging from low to high expression [1-76 rolling circle products (RCPs)/CTC]. In PaCa patients, 40% (6 of 15) had KRAS mut expressing CTCs with 1 to 8 RCPs/CTC. In situ padlock probe analysis revealed CTCs with no detectable cytokeratin expression but positivity for AR-V7 or KRAS mut transcripts.

    CONCLUSIONS: Padlock probe technology enables quantification of AR-V7, AR-FL, PSA, and KRAS mut/wt transcripts in CTCs. The technology is easily applicable in routine laboratories and compatible with multiple CTC-isolation devices.

  • 32. Estampador, Angela C.
    et al.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA; Oxford Center for Diabetes, Endocrinology, and Metabolism, Radcliff Department of Medicine, University of Oxford, Oxford, UK.
    Precision Medicine in Obesity and Type 2 Diabetes: The Relevance of Early-Life Exposures2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 130-141Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Type 2 diabetes is highly prevalent and devastating. Obesity is a diabetogenic factor, driving insulin resistance and a compensatory demand for increased insulin secretion from the pancreatic β cells; a failure to address this demand results in diabetes. Accordingly, primary and secondary prevention of obesity are at the core of diabetes prevention programs. The development of obesity and declining β-cell function often span many years or decades before diabetes is clinically manifest. Thus, characterizing the early-life process and risk factors that set disease trajectories may yield novel targets for early intervention and help improve the accuracy of prediction algorithms, factors germane to the emerging field of precision medicine.

    CONTENT: Here, we overview the concepts of precision medicine and fetal programming. We discuss the barriers to preventing obesity and type 2 diabetes in adulthood and present the rationale for considering early-life events in this context. In so doing, we discuss proof-of-concept studies and cutting-edge technological developments that are likely to transform current thinking on the etiology and pathogenesis of obesity and type 2 diabetes. We also review the factors hampering progress, including the success and failures of pregnancy intervention trials.

    SUMMARY: Obesity and type 2 diabetes are among the major health and economic burdens of our time. Defeating these diseases is likely to require life-course approaches, which may include aggressive interventions informed by biomarker profiling undertaken during early life.

  • 33. Fredriksson, Simon
    et al.
    Horecka, Joe
    Brustugun, Odd Terje
    Schlingemann, Jörg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Koong, Albert C.
    Tibshirani, Rob
    Davis, Ronald W.
    Multiplexed proximity ligation assays to profile putative plasma biomarkers relevant to pancreatic and ovarian cancer2008In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 54, no 3, p. 582-589Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sensitive methods are needed for biomarker discovery and validation. We tested one promising technology, multiplex proximity ligation assay (PLA), in a pilot study profiling plasma biomarkers in pancreatic and ovarian cancer. METHODS: We used 4 panels of 6- and 7-plex PLAs to detect biomarkers, with each assay consuming 1 mu L plasma and using either matched monoclonal antibody pairs or single batches of polyclonal antibody. Protein analytes were converted to unique DNA arnplicons by proximity ligation and subsequently detected by quantitative PCR. We profiled 18 pancreatic cancer cases and 19 controls and 19 ovarian cancer cases and 20 controls for the following proteins: a disintegrin and metalloprotease 8, CA-125, CA 19-9, carboxypeptidase A1, carcinoembryonic antigen, connective tissue growth factor, epidermal growth factor receptor, epithelial cell adhesion molecule, Her2, galectin-1, insulin-like growth factor 2, interleukin-1 alpha, interleukin-7, mesothelin, macrophage migration inhibitory factor, osteopontin, secretory leukocyte peptidase inhibitor, tumor necrosis factor a, vascular endothelial growth factor, and chitinase 3-like 1. Probes for CA-125 were present in 3 of the multiplex panels. We measured plasma concentrations of the CA-125-mesothelin complex by use of a triple-specific PLA with 2 ligation events among 3 probes. RESULTS: The assays displayed consistent measurements of CA-125 independent of which other markers were simultaneously detected and showed good correlation with Luminex data. In comparison to literature reports, we achieved expected results for other putative markers. CONCLUSION: Multiplex PLA using either matched monoclonal antibodies or single batches of polyclonal. antibody should prove useful for identifying and validating sets of putative disease biomarkers and finding. multimarker panels.

  • 34.
    Fremner, E
    et al.
    Div Clin Chem, Linkoping, Sweden.
    Larsson, Lasse
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry.
    Organization of point-of-care testing (POCT) - An administrative challenge.2000In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 46, no 6, p. 25-Conference paper (Other academic)
  • 35. Grubb, Anders
    et al.
    Horio, Masaru
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Björk, Jonas
    Nyman, Ulf
    Flodin, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Bökenkamp, Arend
    Yasuda, Yoshinari
    Blufpand, Hester
    Lindström, Veronica
    Zegers, Ingrid
    Althaus, Harald
    Blirup-Jensen, Søren
    Itoh, Yoshi
    Sjöström, Per
    Nordin, Gunnar
    Christensson, Anders
    Klima, Horst
    Sunde, Kathrin
    Hjort-Christensen, Per
    Armbruster, David
    Ferrero, Carlo
    Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 7, p. 974-986Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays.

    METHODS:

    Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR.

    RESULTS:

    We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C.

    CONCLUSIONS:

    A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

  • 36.
    Gustafsdottir, Sigrun M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordengrahn, Ann
    Fredriksson, Simon
    Wallgren, Per
    Rivera, Esteban
    Schallmeiner, Edith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Merza, M.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Detection of individual microbial pathogens by proximity ligation2006In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 52, no 6, p. 1152-1160Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Nucleic acid amplification allows the detection of single infectious agents. Protein-based assays, although they provide information on ongoing infections, have substantially less detection sensitivity.

    METHODS: We used proximity ligation reactions to detect proteins on bacteria and virus particles via nucleic acid amplification. Antibodies recognizing viral or bacterial surface proteins were equipped with DNA strands that could be joined by ligation when several antibodies were bound in proximity to surface proteins of individual infectious agents.

    RESULTS: Detection sensitivities similar to those of nucleic acid-based detection reactions were achieved directly in infected samples for a parvovirus and an intracellular bacterium.

    CONCLUSIONS: This method enables detection of ligated DNA strands with good sensitivity by real-time PCR and could be of value for early diagnosis of infectious disease and in biodefense.

  • 37.
    Gustafsdottir, Sigrun M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wennström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fredriksson, Simon
    Schallmeiner, Edith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hamilton, Andrew D
    Sebti, Said M
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Use of Proximity Ligation to Screen for Inhibitors of Interactions between Vascular Endothelial Growth Factor A and Its Receptors2008In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 54, no 7, p. 1218-1225Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Improved methods are required to screen drug candidates for their influences on protein interactions. There is also a compelling need for miniaturization of screening assays, with attendant reductions in reagent consumption and assay costs. METHODS: We used sensitive, miniaturized proximity ligation assays (PLAs) to monitor binding of vascular endothelial growth factor A (VEGF-A) to 2 of its receptors, VEGFR-1 and VEGFR-2. We measured the effects of proteins and low molecular weight compounds capable of disrupting these interactions and compared the results with those obtained by immunoblot analysis. We analyzed 6 different inhibitors: a DNA aptamer, a mixed DNA/RNA aptamer, a monoclonal VEGF-A neutralizing antibody, a monoclonal antibody directed against VEGFR-2, a recombinant competitive protein, and a low molecular weight synthetic molecule. RESULTS: The PLAs were successful for monitoring the formation and inhibition of VEGF-A-receptor complexes, and the results correlated well with those obtained by measuring receptor phosphorylation. The total PLA time is just 3 hours, with minimal manual work and reagent additions. The method allows evaluation of the apparent affinity [half-maximal inhibitory concentration (IC(50))] from a dose-response curve. CONCLUSIONS: The PLA may offer significant advantages over conventional methods for screening the interactions of ligands with their receptors. The assay may prove useful for parallel analyses of large numbers of samples in the screening of inhibitor libraries for promising agents. The technique provides dose-response curves, allowing IC(50) values to be calculated.

  • 38.
    Haglund, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences.
    Lindqvist Appell, Malin
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Taipalensuu, J.
    Div. of R. and D. in Lab. Medicine, Ryhov County Hospital, SE-551 85 Jönköping, Sweden.
    Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease2004In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 50, no 2, p. 288-295Article in journal (Refereed)
    Abstract [en]

    Background: Interindividual differences in therapeutic efficacy in patients treated with thiopurines might be explained by the presence of thiopurine S-methyltransferase (TPMT) alleles that encode for reduced TPMT enzymatic activity. It is therefore of value to know an individual's inherent capacity to express TPMT. Method: We developed a pyrosequencing method to detect 10 single-nucleotide polymorphisms (SNPs) in TPMT. A Swedish population (n = 800) was examined for TPMT*3A, TPMT*3B, TPMT*3C, and TPMT*2. Patients with inflammatory bowel disease (n = 24) and healthy volunteers (n = 6), selected on the basis of TPMT enzymatic activity, were investigated for all 10 SNPs to determine the relationship between TPMT genotype and phenotype. Results: In the general population we identified the following genotypes with nonfunctional alleles: TPMT*1/*3A (*3A allelic frequency, 3.75%), TPMT*1/*3C (*3C allelic frequency, 0.44%), TPMT*1/*3B (*3B allelic frequency, 0.13%), and TPMT*1/*2 (*2 allelic frequency, 0.06%). All nine individuals with normal enzymatic activity were wild-type TPMT*1/*1. Thirteen individuals with intermediate activity were either TPMT*1/*3A (n = 12) or TPMT*1/*2 (n = 1). Eight individuals with low enzymatic activity were TPMT*3A/*3A (n = 4), TPMT*3A/*3C (n = 2), or TPMT*1/*3A (n = 2). Conclusion: Next to wild type, the most frequent alleles in Sweden are TPMT*3A and TPMT*3C. A previously established phenotypic cutoff for distinguishing normal from intermediate metabolizers was confirmed. To identify the majority of cases (90%) with low or intermediate TPMT activity, it was sufficient to analyze individuals for only 3 of the 10 SNPs investigated. Nevertheless, this investigation indicates that other mutations might be of relevance for decreased enzymatic activity. © 2004 American Association for Clinical Chemistry.

  • 39.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Stewart, Ralph A H
    Aylward, Philip E
    Budaj, Andrzej
    Cannon, Christopher P
    Koenig, Wolfgang
    Krug-Gourley, Sue
    Mohler, Emile R
    Steg, Philippe Gabriel
    Tarka, Elizabeth
    Östlund, Ollie
    White, Harvey D
    Siegbahn, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Growth Differentiation Factor 15 Predicts All-Cause Morbidity and Mortality in Stable Coronary Heart Disease2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 1, p. 325-333Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Higher growth differentiation factor 15 (GDF-15) concentrations are associated with cardiovascular (CV) and non-CV morbidity and mortality. However, information on associations between GDF-15 and the risk of specific CV and non-CV events in stable coronary heart disease (CHD) patients is limited.

    METHODS: In 14 577 patients with stable CHD participating in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial (STABILITY), GDF-15 and other prognostic biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T, cystatin C, and high-sensitivity C-reactive protein) were measured. In adjusted Cox regression models, the associations between GDF-15 and the composite CV end point [CV death, myocardial infarction (MI), and stroke], as well as other CV and non-CV events, were assessed.

    RESULTS: The median concentration (interquartile range) of GDF-15 at baseline was 1253 (915-1827) ng/L. The hazard ratio for the composite end point for the highest compared to the lowest quartile of GDF-15 was 1.8 (95% CI, 1.5-2.2); for CV death, 2.63 (1.9-3.6); for sudden death, 3.06 (1.9-4.8); for heart failure (HF) death, 4.3 (1.3-14); for cancer death, 2.5 (1.3-4.7); for hospitalization for HF, 5.8 (3.2-10); for MI 1.4 (95% CI, 1.1-1.9); and for stroke, 1.8 (95% CI, 1.1-2.8). After adjustment for other prognostic biomarkers, GDF-15 remained significantly associated with all outcomes except for MI.

    CONCLUSIONS: In stable CHD, GDF-15 was independently associated with CV, non-CV, and cancer mortality, as well as with MI and stroke. When also adjusting for other prognostic biomarkers, the associations to all fatal and nonfatal events were maintained except for MI. Information on GDF-15, therefore, might be helpful when assessing the risk of adverse outcomes in patients with stable CHD. ClinicalTrials.gov Identifier: NCT00799903.

  • 40.
    Hartmann, Michael
    et al.
    NMI–Natural and Medical Sciences Institute at the University of Tübingen.
    Schrenk, Monika
    Dottinger, Anette
    Nagel, Sarah
    Roeraade, Johan
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Analytical Chemistry.
    Joos, Thomas O.
    Templin, Markus F.
    Expanding assay dynamics: A combined competitive and direct assay system for the quantification of proteins in multiplexed Immunoassays2008In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 54, no 6, p. 956-963Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The concurrent detection and quantification of analytes that vary widely in concentration present a principal problem in multiplexed assay systems. Combining competitive and sandwich immunoassays permits coverage of a wide concentration range, and both highly abundant molecules and analytes present in low concentration can be quantified within the same assay. METHODS: The use of different fluorescence readout channels allows the parallel use of a competitive system and a sandwich configuration. The 2 generated assay signals are combined and used to calculate the amount of analyte. The measurement range can be adjusted by varying the competitor concentration, and an extension of the assay system's dynamic range is possible. RESULTS: We implemented the method in a planar protein microarray-based autoimmune assay to detect autoantibodies against 13 autoantigens and to measure the concentration of a highly abundant protein, total human IgG, in one assay. Our results for autoantibody detection and IgG quantification agreed with results obtained with commercially available assays. The use of 2 readout channels in the protein microarray-based system reduced spot-to-spot variation and intraassay variation. CONCLUSIONS: By combining a direct immunoassay with a competitive system, analytes present in widely varying concentrations can be quantified within a single multiplex assay. Introducing a second readout channel for analyte quantification is an effective tool for spot-to-spot normalization and helps to lower intraassay variation.

  • 41. Hickman, Peter E.
    et al.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Potter, Julia M.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Koerbin, Gus
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Is It Time to Do Away With the 99th Percentile for Cardiac Troponin in the Diagnosis of Acute Coronary Syndrome and the Assessment of Cardiac Risk?2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 5, p. 734-736Article in journal (Other academic)
  • 42. Hietala, M
    et al.
    Aula, P
    Syvänen, Ann-Christine
    Isoniemi, A
    Peltonen, L
    Palotie, A
    DNA-based carrier screening in primary healthcare: screening for aspartylglucosaminuria mutations in maternity health offices1996In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 42, no 9, p. 1398-1404Article in journal (Refereed)
    Abstract [en]

    Large-scale genetic screening programs are complex enterprises in which ethical, technical, medical, and socioeconomic aspects have to be handled with professional expertise. Establishment of automated, relatively robust, and inexpensive laboratory techniques is one step of this path. Here a pilot carrier-screening program for the mutations causing aspartylglucosaminuria was carried out for pregnant women in primary care maternity health offices. Women (1975) were tested before their 12th week of pregnancy, and 31 heterozygotes were detected. The sampling was based on dried blood strips, facilitating convenient handling and inexpensive mailing to the laboratory. The mutation detection technique, solid-phase mini-sequencing simplified by the use of scintillation microplates and automated equipment, proved to be rapid, simple, inexpensive, and reliable, with a low repeat rate (2.5%). In conclusion, we found that good collaboration between the primary healthcare unit, the laboratory, and counseling experts, combined with modern laboratory technology, facilitate reliable low-cost genetic testing.

  • 43.
    Hijazi, Ziad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Application of Biomarkers for Risk Stratification in Patients with Atrial Fibrillation2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 11, p. 152-164Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Atrial fibrillation is the most common sustained arrhythmia and an important contributor to cardiovascular morbidity and mortality. Several strategies have been proposed for prediction of outcomes and individualization of treatments to better balance the benefits of stroke prevention and risks of bleeding during anticoagulation. CONTENT: The availability of analytically more specific and sensitive methods to measure circulating biomarkers of cellular and organ stress and dysfunction has led to testing of their utility in several cardiovascular conditions. In patients with atrial fibrillation, biomarkers of myocardial injury (troponin) and cardiovascular stress and dysfunction (natriuretic peptides, growth differentiation factor 15), myocardial fibrosis (galectin-3), renal dysfunction (creatinine, cystatin C), inflammation (C reactive protein, cytokines) and coagulation activity (D-dimer) have been found associated with underlying pathophysiology, clinical outcomes and effects of treatment. Measurements of these markers might therefore expand the understanding of the pathophysiology, improve risk assessment and optimize treatment in individual patients with atrial fibrillation. SUMMARY: Biomarkers for risk stratification have potential roles as tools for evaluation of patients with atrial fibrillation and for selection of the best treatment strategies to prevent stroke, major bleeding, and mortality.

  • 44.
    Hijazi, Ziad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Granger, Christopher
    Duke Clinical Research Institute, Durham, NC, US.
    Alexander, John H
    Duke Clinical Research Institute, Durham, NC, US.
    Atar, Dan
    Department of Cardiology, Oslo University Hospital Ulleval and Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, Norway.
    Gersh, Bernard
    Mayo Clinic College of Medicine, Rochester, MN, US.
    Hanna, Michael
    Bristol-Myers Squibb, Princeton, NJ, US.
    Harjola, Veli-Pekka
    Horowitz, John D
    Hylek, Elaine M
    Lopes, Renato D
    McMurray, John JV
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Comparison of Cardiac Troponins I and T Measured with High-Sensitivity Methods for Evaluation of Prognosis in Atrial Fibrillation: An ARISTOTLE Substudy2015In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 61, no 2, p. 368-378Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Although cardiac troponin is associated with outcomes in atrial fibrillation (AF), the complementary prognostic information provided by cardiac troponin I (cTnI) and cTnT is unknown. This study investigated the distribution, determinants, and prognostic value of cTnI and cTnT concentrations in patients with AF.

    METHODS:

    At the time of randomization, we analyzed cTnI and cTnT concentrations of 14 806 AF patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial using high-sensitivity assays. Correlations (Spearman), determinants (multiple analysis of variance), and outcomes (adjusted Cox models and c-statistics) were investigated.

    RESULTS:

    Concentrations of cTnI and cTnT were correlated (r = 0.70) and measurable in most participants [cTnI 98.5% (median 5.4 ng/L, ≥99th percentile in 9.2%) and cTnT 93.5% (median 10.9 ng/L, ≥99th percentile in 34.4%)]. Renal impairment was the most important factor affecting the concentrations of both troponins. cTnI increase was more associated with heart failure, vascular disease, and persistent/permanent AF, and cTnT with age, male sex, and diabetes. Over a median 1.9 years of follow-up, patients with both troponins above the median had significantly higher risk for stroke/systemic embolism [hazard ratio (HR) 1.72 (95% CI 1.31-2.27)], cardiac death [3.14 (2.35-4.20)], and myocardial infarction [2.99 (1.78-5.03)] than those with both troponins below median (all P < 0.005). Intermediate risks were observed when only 1 troponin was above the median. When combined with clinical information, each marker provided similar prognostication and had comparable c-statistics.

    CONCLUSIONS:

    cTnI and cTnT concentrations are moderately correlated and measurable in plasma of most AF patients. The risk of stroke and cardiovascular events is highest when both troponins are above median concentrations. Each troponin provides comparable prognostic information when combined with clinical risk factors.

  • 45.
    Hjort, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Agewall, Stefan
    Univ Oslo, Inst Clin Sci, Oslo Univ Hosp, Oslo, Norway.
    Brolin, Elin B.
    Soder Sjukhuset, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Collste, Olov
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Daniel, Maria
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Ekenbäck, Christina
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Frick, Mats
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Henareh, Loghman
    Karolinska Univ Hosp, Dept Med, Heart & Vasc Theme, Stockholm, Sweden.
    Hofman-Bang, Claes
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Malmqvist, Karin
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Spaak, Jonas
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Sörensson, Peder
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Y-Hassan, Shams
    Karolinska Univ Hosp, Dept Med, Heart & Vasc Theme, Stockholm, Sweden.
    Tornvall, Per
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries2019In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 65, no 8, p. 1023-1030Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD).

    METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age-and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses.

    RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-kappa-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls.

    CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts. 

  • 46. Ho, J. E.
    et al.
    Mahajan, A.
    Chen, M. -H
    Larson, M. G.
    McCabe, E. L.
    Ghorbani, A.
    Cheng, S.
    Johnson, A. D.
    Lindgren, C. M.
    Kempf, T.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ingelsson, E.
    Vasan, R. S.
    Januzzi, J.
    Wollert, K. C.
    Morris, A. P.
    Wang, T. J.
    Clinical and genetic correlates of growth differentiation factor 15 in the community2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 11, p. 1582-1591Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Growth differentiation factor 15(GDF15), a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease (CVD). We therefore examined the clinical and genetic correlates of circulating GDF15 concentrations, which have not been investigated collectively. METHODS: Plasma GDF15 concentrations were measured in 2991 participants in the Framingham Offspring Study who were free of clinically overt CVD (mean age, 59 years; 56% women). Clinical correlates of GDF15 were examined in multivariable analyses. We then conducted a genomewide association study of the GDF15 concentration that included participants in the Framingham Offspring Study and participants in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. RESULTS: GDF15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and use of nonsteroidal antiinflammatory drugs (NSAIDs), but it was negatively associated with total cholesterol and HDL cholesterol. Clinical correlates accounted for 38% of interindividual variation in the circulating GDF15 concentration, whereas genetic factors accounted for up to 38% of the residual variability (h 2 = 0.38; P = 2.5 X 10 -11). We identified 1 locus of genomewide significance. This locus, which is on chromosome 19p13.11 and includes the GDF15 gene, is associated with GDF15 concentration (smallest P = 2.74 X 10 -32 for rs888663). Conditional analyses revealed 2 independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis gene expression in blood cell lines. CONCLUSIONS: In ambulatory individuals, both cardiometabolic risk factors and genetic factors play important roles in determining circulating GDF15 concentrations and contribute similarly to the overall variation.

  • 47. Holmberg, K.
    et al.
    Persson, M. L.
    Uhlén, Mathias
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics.
    Pyrosequencing analysis of thrombosis-associated risk markers2005In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 51, no 8, p. 1549-1552Article in journal (Refereed)
  • 48. Huang, Jiaqi
    et al.
    Löhr, Johannes-Matthias
    Nilsson, Magnus
    Segersvärd, Ralf
    Matsson, Hans
    Verbeke, Caroline
    Heuchel, Rainer
    Kere, Juha
    Iafrate, A John
    Zheng, Zongli
    Ye, Weimin
    Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma.2015In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 61, no 11, p. 1408-16Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Variant profiling is crucial for developing personalized treatment and elucidating the etiology of this disease.

    METHODS: Patients with PDAC undergoing surgery from 2007 to 2012 (n = 73) were followed from diagnosis until death or the end of the study. We applied an anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) method to a panel of 65 selected genes and assessed analytical performance by sequencing a quantitative multiplex DNA reference standard. In clinical PDAC samples, detection of low-level KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations was validated by allele-specific PCR and digital PCR. We compared overall survival of patients according to KRAS mutation status by log-rank test and applied logistic regression to evaluate the association between smoking and tumor variant types.

    RESULTS: The AMP-based NGS method could detect variants with allele frequencies as low as 1% given sufficient sequencing depth (>1500×). Low-frequency KRAS G12 mutations (allele frequency 1%-5%) were all confirmed by allele-specific PCR and digital PCR. The most prevalent genetic alterations were in KRAS (78% of patients), TP53 (tumor protein p53) (25%), and SMAD4 (SMAD family member 4) (8%). Overall survival in T3-stage PDAC patients differed among KRAS mutation subtypes (P = 0.019). Transversion variants were more common in ever-smokers than in never-smokers (odds ratio 5.7; 95% CI 1.2-27.8).

    CONCLUSIONS: The AMP-based NGS method is applicable for profiling tumor variants. Using this approach, we demonstrated that in PDAC patients, KRAS mutant subtype G12V is associated with poorer survival, and that transversion variants are more common among smokers.

  • 49. Huang, Tao
    et al.
    Ding, Ming
    Bergholdt, Helle K. M.
    Wang, Tiange
    Heianza, Yoriko
    Sun, Dian-jianyi
    Frazier-Wood, Alexis C.
    Aslibekyan, Stella
    North, Kari E.
    Voortman, Trudy
    Graff, Mariaelisa
    Smith, Caren E.
    Lai, Chao-Qiang
    Varbo, Anette
    Lemaitre, Rozenn N.
    de Jonge, M. Ester A. L.
    Fumeron, Fredric
    Corella, Dolores
    Wang, Carol A.
    Tjonneland, Anne
    Overvad, Kim
    Sorensen, Thorkild I. A.
    Feitosa, Mary F.
    Wojczynski, Mary K.
    Kahonen, Mika
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Psaty, Bruce M.
    Siscovick, David S.
    Barroso, Ines
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hernandez, Dena
    Ferrucci, Luigi
    Bandinelli, Stefania
    Linneberg, Allan
    Zillikens, M. Carola
    Sandholt, Camilla Helene
    Pedersen, Oluf
    Hansen, Torben
    Schulz, Christina-Alexandra
    Sonestedt, Emily
    Orho-Melander, Marju
    Chen, Tzu-An
    Rotter, Jerome I.
    Allison, Mathew A.
    Rich, Stephen S.
    Sorli, Jose V.
    Coltell, Oscar
    Pennell, Craig E.
    Eastwood, Peter
    Hofman, Albert
    Uitterlinden, Andre G.
    van Rooij, Frank J. A.
    Chu, Audrey Y.
    Rose, Lynda M.
    Ridker, Paul M.
    Viikari, Jorma
    Raitakari, Olli
    Lehtimaki, Terho
    Mikkila, Vera
    Willett, Walter C.
    Wang, Yujie
    Tucker, Katherine L.
    Ordovas, Jose M.
    Kilpelainen, Tuomas O.
    Province, Michael A.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard School of Public Health, Boston, MA; Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Arnett, Donna K.
    Tanaka, Toshiko
    Toft, Ulla
    Ericson, Ulrika
    Franco, Oscar H.
    Mozaffarian, Dariush
    Hu, Frank B.
    Chasman, Daniel I.
    Nordestgaard, Borge G.
    Ellervik, Christina
    Qi, Lu
    Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 183-191Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined.

    METHODS: We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies.

    RESULTS: Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00–0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14–0.25) serving/day higher dairy intake (P = 3.15 × 10−12) and 0.12 (95% CI, 0.06–0.17) kg/m2 higher BMI (P = 2.11 × 10−5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27–0.92; P = 3.0 × 10−4).

    CONCLUSIONS: The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.

  • 50.
    Hunter, Ingrid
    et al.
    University of Copenhagen.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Rehfeld, Jens F.
    University of Copenhagen.
    Crimmins, Dan L.
    Washington University.
    Goetze, Jens P.
    University of Copenhagen.
    N-Terminal Pro-Atrial Natriuretic Peptide Measurement in Plasma Suggests Covalent Modification2011In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 57, no 9, p. 1327-1330Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The N-terminal fragment of cardiac-derived pro-B-type natriuretic peptide is a glycosylated polypeptide. It is unknown whether N-terminal proatrial natriuretic peptide (proANP) fragments are also covalently modified. We therefore evaluated the clinical performance of 2 distinctly different proANP assays on clinical outcome. METHODS: We examined 474 elderly patients with symptoms of heart failure presenting in a primary healthcare setting. Samples were analyzed with an automated immunoluminometric midregion proANP (MR-proANP) assay and a new processing-independent assay (PIA) developed in our laboratory. The results were compared with Bland-Altman plots, and clinical performance was assessed by generating ROC curves for different clinical outcomes. RESULTS: Despite linear regression results indicating a good correlation (r = 0.85; P less than 0.0001), the PIA measured considerably more proANP than the MR-proANP assay (mean difference, 663 pmol/L; SD, 478 pmol/L). In contrast, the clinical performances of the 2 assays [as assessed by the area under the ROC curve (AUC)] in detecting left ventricular dysfunction were similar [proANP PIA, 0.71 (95% CI, 0.63-0.79); MR-proANP assay, 0.74 (95% CI, 0.66-0.81); P = 0.32]. The prognostic ability to report cardiovascular mortality during a 10-year follow-up revealed AUC values of 0.66 (95% CI, 0.60-0.71) for the proANP PIA and 0.69 (95% CI, 0.63-0.74) for the MR-proANP assay (P = 0.08, for comparing the 2 assays). CONCLUSIONS: Our data suggest that N-terminal proANP fragments in patient plasma differ from the calibrator peptides used but that the difference does not affect ROC curves in an elderly cohort of patients with mild to moderate heart failure. We suggest that human N-terminal proANP fragments can be covalently modified.

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