RESUMEN
PURPOSE: A sensitive and specific imaging biomarker to monitor immune activation and quantify pharmacodynamic responses would be useful for development of immunomodulating anti-cancer agents. PF-07062119 is a T cell engaging bispecific antibody that binds to CD3 and guanylyl cyclase C, a protein that is over-expressed by colorectal cancers. Here, we used 89Zr-Df-IAB22M2C (89Zr-Df-Crefmirlimab), a human CD8-specific minibody to monitor CD8+ T cell infiltration into tumors by positron emission tomography. We investigated the ability of 89Zr-Df-IAB22M2C to track anti-tumor activity induced by PF-07062119 in a human CRC adoptive transfer mouse model (with injected activated/expanded human T cells), as well as the correlation of tumor radiotracer uptake with CD8+ immunohistochemical staining. PROCEDURES: NOD SCID gamma mice bearing human CRC LS1034 tumors were treated with four different doses of PF-07062119, or a non-targeted CD3 BsAb control, and imaged with 89Zr-Df-IAB22M2C PET at days 4 and 9. Following PET/CT imaging, mice were euthanized and dissected for ex vivo distribution analysis of 89Zr-Df-IAB22M2C in tissues on days 4 and 9, with additional data collected on day 6 (supplementary). Data were analyzed and reported as standard uptake value and %ID/g for in vivo imaging and ex vivo tissue distribution. In addition, tumor tissues were evaluated by immunohistochemistry for CD8+ T cells. RESULTS: The results demonstrated substantial mean uptake of 89Zr-Df-IAB22M2C (%ID/g) in PF-07062119-treated tumors, with significant increases in comparison to non-targeted BsAb-treated controls, as well as PF-07062119 dose-dependent responses over time of treatment. A moderate correlation was observed between tumor tissue radioactivity uptake and CD8+ cell density, demonstrating the value of the imaging agent for non-invasive assessment of intra-tumoral CD8+ T cells and the mechanism of action for PF-07062119. CONCLUSION: Immune-imaging technologies for quantitative cellular measures would be a valuable biomarker in immunotherapeutic clinical development. We demonstrated a qualification of 89Zr-IAB22M2C PET to evaluate PD responses (mice) to a novel immunotherapeutic.
Asunto(s)
Tomografía Computarizada por Tomografía de Emisión de Positrones , Circonio , Animales , Biomarcadores , Línea Celular Tumoral , Ratones , Ratones SCID , Tomografía de Emisión de Positrones/métodos , Receptores de Enterotoxina , Linfocitos TRESUMEN
BACKGROUND: Effective treatments for managing suboptimal clinical responses to current therapy for schizophrenia remain a critical unmet need. Phosphodiesterase 10A (PDE10A) inhibition represents a mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920. Therefore, the adjunctive safety, tolerability, pharmacokinetics, and efficacy of multiple repeat doses of PF-02545920 were investigated in a phase 1b study and subsequent phase 2 study. METHODS: The phase 1b study randomized 37 adult patients with stable symptomatology and stable antipsychotic regimens within 3 cohorts. Study participants received ascending doses of PF-02545920 or placebo for 10 to 18 days. The phase 2 study randomized 240 outpatients with stable symptomatology but suboptimal response to current antipsychotic regimens 1:1:1 to PF-02545920 5 mg, PF-02545920 15 mg, or placebo every 12 hours for 12 weeks. The primary efficacy end point of the phase 2 study was change in the Positive and Negative Syndrome Scale total score from baseline to week 12, with changes in other clinical assessments as secondary end points. RESULTS: Treatment was well tolerated, and observed PF-02545920 exposures were within the range predicted to be adequate for demonstrating efficacy. However, no significant differences in the prespecified efficacy end points between the 2 PF-02545920 treatment arms and placebo were observed. CONCLUSIONS: Current data and results of a prior monotherapy study in which PF-02545920 failed to differentiate from placebo refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for schizophrenia.
Asunto(s)
Inhibidores de Fosfodiesterasa/uso terapéutico , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración PsiquiátricaRESUMEN
Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects and complex disease associations in the same locus.
RESUMEN
Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Clusterina/líquido cefalorraquídeo , Endofenotipos , Estudio de Asociación del Genoma Completo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/fisiopatología , Apolipoproteína E4 , Apolipoproteínas E/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Clusterina/sangre , Clusterina/fisiología , Femenino , Ontología de Genes , Humanos , Inmunidad/genética , Masculino , Degeneración Nerviosa/genética , Cicatrización de Heridas/genéticaRESUMEN
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aß42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.
Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Metaloproteinasa 3 de la Matriz/genética , Renina/genética , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas Sanguíneas/genética , Quimiocina CCL2/genética , Quimiocina CCL4/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Factor de Crecimiento Nervioso/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-6/genética , Receptores de Lipoproteína/genética , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genéticaRESUMEN
BACKGROUND: Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. METHODS: A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aß42 was used as a continuous trait in these analyses. RESULTS: The ptau181-Aß42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aß42) compared with elderly control subjects with no pathology (low ptau181, high Aß42). The FABP-Aß42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aß42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. CONCLUSIONS: Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Estudios de Cohortes , Progresión de la Enfermedad , Proteína 3 de Unión a Ácidos Grasos , Proteínas de Unión a Ácidos Grasos/líquido cefalorraquídeo , Femenino , Humanos , Inmunoensayo/métodos , Oxidorreductasas Intramoleculares/líquido cefalorraquídeo , Estimación de Kaplan-Meier , Factores Inhibidores de la Migración de Macrófagos/líquido cefalorraquídeo , Masculino , Análisis Multivariante , Fosforilación , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/líquido cefalorraquídeoRESUMEN
The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10(-4)) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aß(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aß(42) levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aß(42) levels was independent of the APOE ε4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ε4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10(-13)). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ε4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10(-6). Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10(-9)).
Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/líquido cefalorraquídeo , Apolipoproteínas E/genética , Fenotipo , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: We characterized tear protein markers in dry eye disease (DED). METHODS: In this prospective study, based on the ocular surface disease index (OSDI) and corneal staining (CS), 95 DED patients (OSDI ≥13) with increasing CS were enrolled into 3 severity groups: DE1 (CS <4), DE2 (CS 4-7), and DE3 (CS >7), while 25 asymptomatic subjects with no CS were enrolled into the control group (OSDI <13 and CS = 0). Tear fluid was collected at day 0 and day 7 visits, and concentrations of 43 protein markers were measured by multiplexed immunoassay. RESULTS: We analyzed 22 control and 80 DED subjects. Among 33 markers detectable, good inter-visit repeatability was observed with 25 markers, with intraclass correlation coefficients (ICC) ranging from 0.85-0.60; ICCs were <0.60 in the other 8. Correlation with clinical measures was found with two markers, with absolute partial correlation coefficients >0.40: Interleukin-1 receptor antagonist (IL-1Ra) and IL-8. IL-1Ra and IL-8 correlated with conjunctival staining (0.43, P < 0.001 and 0.35, P < 0.01, respectively), and with Schirmer test (-0.58 and -0.42, P < 0.001). IL-1Ra and IL-8 in DE3 were 4.4- and 2.1-fold higher than in DE1 (P = 0.0001 and 0.0007), and 1.9- and 1.6-fold higher than in DE2 (P = 0.022 and 0.017). IL-1Ra in DE2 was 2.3-fold higher than in DE1 (P = 0.038). CONCLUSIONS: Tear levels of many immune mediators were highly repeatable between visits in DED. Among them, IL-1Ra and IL-8 were associated with clinical signs and disease severity defined by corneal staining.
Asunto(s)
Síndromes de Ojo Seco/diagnóstico , Proteínas del Ojo/análisis , Lágrimas/química , Adulto , Biomarcadores/análisis , Síndromes de Ojo Seco/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To evaluate the immunomodulatory effect of topical ophthalmic tofacitinib (CP-690,550) after an 8-week treatment period in patients with dry eye disease (DED). DESIGN: Biomarker substudy of a phase 1/2 prospective, randomized, vehicle- and comparator-controlled clinical trial (NCT00784719). PARTICIPANTS: A total of 82 patients with moderate to severe DED enrolled. METHODS: Patients received 1 of 5 doses of tofacitinib (0.0003%, 0.001%, 0.003%, or 0.005% twice daily [BID] or 0.005% once daily [QD]), active comparator (cyclosporine ophthalmic emulsion, 0.05% [Restasis, Allergan Inc., Irvine, CA]), or vehicle control BID for 8 weeks. Conjunctival impression cytology and tear fluid samples were collected at baseline and after an 8-week treatment period. Conjunctival cells were analyzed by flow cytometry for human leukocyte antigen DR-1 (HLA-DR). Tear fluids were analyzed by microsphere-based immunoassays for tear levels of cytokines and inflammation markers. MAIN OUTCOME MEASURES: Reduction in inflammation assessed by change from baseline in conjunctival cell surface level of HLA-DR and tear level of cytokines and inflammation markers. RESULTS: At week 8, a decrease in conjunctival cell surface expression of HLA-DR was observed in patients treated with tofacitinib 0.005% QD and 0.003% BID: 71% and 67% of baseline, respectively, compared with 133% of baseline in patients treated with vehicle (P=0.023 and P=0.006, compared with vehicle, respectively). Matrix metalloproteinase (MMP)-3 in tears was reduced from baseline at week 8 (40% of baseline, P=0.035) in the tofacitinib 0.005% QD group, whereas the vehicle group showed 77% of baseline (P>0.20). Interleukin (IL)-1ß in tears was 36% of baseline (P=0.053) in the tofacitinib 0.005% QD group and 95% of baseline (P > 0.20) in the vehicle group. Several other cytokines and inflammation markers in tears, including MMP-9, IL-15, IL-17A, and IL-12p70, were markedly reduced in the tofacitinib 0.005% QD group but not the vehicle group. There was an association between the changes in HLA-DR and the tear inflammation markers (P<0.05): HLA-DR with IL-12p70 (r=0.49) and IL-1ß (r=0.46), IL-12p70 with IL-1ß (r=0.90), and IL-17A with MMP-9 (r=0.82). CONCLUSIONS: Topical ophthalmic tofacitinib may act as an immunomodulator in patients with DED. Treatment for 8 weeks showed a promising reduction of conjunctival cell surface HLA-DR expression and tear levels of proinflammatory cytokines and inflammation markers.
Asunto(s)
Síndromes de Ojo Seco/tratamiento farmacológico , Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Administración Tópica , Conjuntiva/metabolismo , Ciclosporina/administración & dosificación , Citocinas/metabolismo , Síndromes de Ojo Seco/metabolismo , Femenino , Citometría de Flujo , Antígeno HLA-DR1/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas , Piperidinas , Lágrimas/metabolismoRESUMEN
BACKGROUND: Clinicopathological studies suggest that Alzheimer's disease (AD) pathology begins â¼10-15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (Aß42, tau, p-tau181). METHODS AND FINDINGS: Using a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO-α, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/Aß42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, Aß42, and age. CONCLUSIONS/SIGNIFICANCE: Using a targeted proteomic screen, we identified novel candidate biomarkers that complement the best current CSF biomarkers for distinguishing very mildly/mildly demented from cognitively normal individuals. Additionally, we identified a novel biomarker (calbindin) with significant prognostic potential.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Inmunoensayo/métodos , Algoritmos , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Inteligencia Artificial , Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/complicaciones , Demografía , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROCRESUMEN
The deposition of amyloid beta peptide (Abeta) in the form of plaques in the brain is a hallmark of Alzheimer's disease (AD). Neprilysin is the major Abeta-degradating enzyme and reduction in neprilysin activity could contribute to Alzheimer's by increasing the steady-state level of Abeta. To provide further evidence for the role of neprilysin in AD we genotyped 22 polymorphisms, 21 SNPs and the GT repeat in the promoter region, across the neprilysin gene in 298 Caucasian sporadic Alzheimer's patients and 298 age-matched controls. Several SNPs showed genotypic and allelic association to AD. SNP rs1836915, in linkage disequilibrium block 2, showed the greatest extent of genotypic association with AD (p=0.0076). We were unable to replicate any of the SNPs that were previously reported as putatively associated with AD. However, these novel findings add to the weight of evidence supporting the involvement of neprilysin in the aetiology of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/genética , Desequilibrio de Ligamiento , Neprilisina/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Población Blanca/genéticaRESUMEN
BACKGROUND: The objective of the study was to quantify the accuracy and reproducibility of five commercially available pulmonary function test (PFT) instruments (Collins CPL [Ferraris Respiratory; Louisville, CO]; Morgan Transflow Test PFT System [Morgan Scientific; Haverhill, MA]; SensorMedics Vmax 22D [VIASYS Healthcare; Yorba Linda, CA]; Jaeger USA Masterscreen Diffusion TP [VIASYS Healthcare]; and Medical Graphics Profiler DX System [Medical Graphics Corp; St. Paul, MN]) that are associated with spirometry and the measurement of pulmonary diffusing capacity. METHODS: In a multifactor, single-center, repeated-measures, full factorial 90-day study, a pulmonary waveform generator and a single-breath simulator of diffusing capacity of the lung for carbon monoxide (Dlco) were used to perform simulations of FVC and Dlco maneuvers. Accuracy was assessed as the difference between the observed and simulated values. Reproducibility was determined as the coefficient of variation of all measurements made during the study. RESULTS: All instruments demonstrated a high degree of accuracy in the measurement of FVC and FEV(1). Overall, the accuracies associated with the measurement of peak flow, forced expiratory flow, mid-expiratory phase, and diffusing capacity were generally lower and more variable among the instruments tested. The coefficients of variation of Dlco measurements over 90 days were higher than those observed for spirometry. CONCLUSIONS: This study demonstrates the feasibility of assessing the accuracy and reproducibility of modern PFT instruments using simulation testing. Our results provide an assessment of the component of PFT accuracy and reproducibility that is due to instrumentation alone.
Asunto(s)
Dióxido de Carbono/metabolismo , Simulación por Computador , Pulmón/fisiología , Capacidad Vital/fisiología , Diseño de Equipo , Estudios de Factibilidad , Estudios de Seguimiento , Humanos , Capacidad de Difusión Pulmonar/instrumentación , Capacidad de Difusión Pulmonar/normas , Reproducibilidad de los Resultados , Espirometría/instrumentación , Espirometría/normasRESUMEN
BACKGROUND: The objective of the study was to characterize the biological and technical components of variability associated with longitudinal measurements of FEV(1) and carbon monoxide diffusing capacity (Dlco). Variability was apportioned to subject and instrument for five commercially available pulmonary function testing (PFT) systems: Collins CPL (Ferraris Respiratory; Louisville, CO); Morgan Transflow Test PFT System (Morgan Scientific; Haverhill, MA); SensorMedics Vmax 22D (VIASYS Healthcare; Yorba Linda, CA); Jaeger USA Masterscreen Diffusion TP (VIASYS Healthcare; Yorba Linda, CA); and Medical Graphics Profiler DX System (Medical Graphics Corporation; St. Paul, MN). METHODS: This was a randomized, replicated cross-over, single-center methodology study in 11 healthy subjects aged 20 to 65 years. Spirometry and Dlco measurements were performed at baseline, 3 months, and 6 months. Repetitive simulations of FEV(1) and Dlco were performed on the same instruments on four occasions over a 90-day period using a spirometry waveform generator and a Dlco simulator. RESULTS: The coefficient of variation associated with repetitive measurements of FEV(1) or Dlco in subjects was consistently larger than that associated with repetitive simulated waveforms across the five instruments. Instrumentation accounted for 13 to 58% of the total FEV(1) and 36 to 70% of the total Dlco variability observed in subjects. Sample size estimates of hypothetical studies designed to detect treatment group differences of 0.050 L in FEV(1) and 0.5 mL/min/mm Hg in Dlco varied as much as four times depending on the instrument utilized. CONCLUSIONS: These results provide a semiquantitative assessment of the biological and technical components of PFT variability in a highly standardized setting. They illustrate how instrument choice and test variability can impact sample size determinations in clinical studies that use FEV(1) and Dlco as end points.
Asunto(s)
Dióxido de Carbono/metabolismo , Volumen Espiratorio Forzado/fisiología , Pulmón/fisiología , Adulto , Anciano , Simulación por Computador , Estudios Cruzados , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Capacidad de Difusión Pulmonar/fisiología , Valores de Referencia , Reproducibilidad de los Resultados , Espirometría/métodos , Factores de TiempoRESUMEN
BACKGROUND: Schizophrenia is a complex psychiatric disorder with a strong genetic component. Past linkage studies have implicated several chromosomal regions in the etiology of schizophrenia. Within these regions, several genes have been identified via candidate gene association studies as strong schizophrenia susceptibility loci, including DAO, DAOA, DISC1, DTNBP1, and RGS4. METHODS: The present study attempted to replicate these association findings by analyzing a total of 120 markers across these genes in 311 schizophrenia subjects, 140 schizoaffective subjects, and 291 control subjects. RESULTS: Our study found no association for DAOA and DTNBP1 with schizophrenia. Although no association was seen with DAOA and DTNBP1, several other markers in the other genes resulted in significant association with schizophrenia (p < .05). However, after a conservative Bonferroni correction for multiple testing, only one marker, rs3918346, within DAO remained significant (odds ratio = 1.71, confidence interval = 1.32-2.22, p = 4 x 10(-5)). This significant association was concordant with previous DAO genetic findings. CONCLUSIONS: Our results significantly support DAO as a susceptibility locus for schizophrenia and offer some support for the implication of both RGS4 and DISC1 in the etiology of schizophrenia. However, we see no evidence to support either DAOA or DTNBP1 as schizophrenia disease loci.
Asunto(s)
D-Aminoácido Oxidasa/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Trastornos Psicóticos/genética , Esquizofrenia/genética , Proteínas Portadoras/genética , Mapeo Cromosómico , Disbindina , Proteínas Asociadas a la Distrofina , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteínas del Tejido Nervioso/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Trastornos Psicóticos/diagnóstico , Proteínas RGS/genética , Esquizofrenia/diagnósticoRESUMEN
The cholesteryl ester transfer protein gene (CETP) has been the subject of hundreds of genetic analyses that typically focus on a small number of polymorphisms within a single ethnic group. Furthermore, the extent of DNA beyond the transcribed sequence from which single nucleotide polymorphisms (SNPs) may influence CETP expression has not been well defined. To better understand the role of natural variation in modulating CETP and high density lipoprotein-cholesterol (HDL-C) levels, dense genotyping of CETP and regions up to 15 kb on either side of the gene was carried out on >2,000 individuals. A complex, nonlinear set of linkage disequilibrium bins was found, with many bins interspersed along the DNA sequence and spread over large regions of the gene. Bins assigned based on large numbers of individuals matched the small subset of SNPs that had been assigned to bins previously with a small number of individuals. Associations of known functional SNPs with HDL-C were found, but there were suggestions that there are additional functional SNPs not characterized previously. Narrowing of the set of likely functional SNPs was accomplished by comparing associations observed in different ethnic groups. The promoter SNP most highly associated with HDL-C that is likely to be functional, position -4,502, alters a consensus transcription factor binding site.