Pharmacogenetic analysis of belimumab fails to identify robust genetic predictors of efficacy in lupus.

GlaxoSmithKline (GSK) conducted pharmacogenetic (PGx) analyses to determine whether genetic variants influence response to belimumab treatment in patients with systemic lupus erythematosus (SLE). We conducted an exploratory genome-wide meta-analysis (GWAS) of 10.9 million genetic variants and the efficacy data from 816 belimumab-treated SLE patients in three phase 3 belimumab clinical studies. Two highly correlated variants, rs293983 and rs364370, in the ANO3 (anoctamin 3) gene region were significantly associated with efficacy as measured by the SLE Response Index (SRI4) with a per-T-allele odds ratio (OR) of 2.15 [95% confidence interval (CI): 1.66-2.79, P=8.0×10]. In contrast, there was no association with SRI4 response in 577 placebo-treated patients (per-T-allele OR: 0.98; 95% CI: 0.74-1.29, P=0.87). A post-hoc analysis by geographic region revealed a strong SRI4 response signal in 157 belimumab-treated patients from Asia (per-T-allele OR=2.85, 95% CI: 1.41-5.74, P=0.0021). On the basis of this encouraging finding in Asian patients, we conducted a confirmatory analysis of the SRI4 end point in an independent phase 3 study of SLE patients from northeast Asia. We found no evidence of an association between rs293983 and SRI4 response in 204 belimumab-treated patients (per-T-allele OR: 0.90, 95% CI: 0.52-1.57, P=0.64). The inability to replicate the observed GWAS effect suggests this was a false positive result; hence, we failed to identify any genetic variants significantly associated with belimumab efficacy.

Assessment of yoga as an adjuvant treatment for combat-related posttraumatic stress disorder.

OBJECTIVES: This study assessed yoga as an adjuvant strategy for symptoms of combat-related posttraumatic stress disorder (PTSD). METHODS: Subjects had significant, combat-related PTSD. Control data were collected during an eight-week waiting period. Trauma-sensitive yoga sessions of 90 minutes duration were provided every seven days for eight weeks. Assessments included the PTSD checklist (PCL); the Depression, Anxiety and Stress Scale (DASS); the Pittsburgh Sleep Quality Index (PSQI); the Adult/Adolescent Sensory Profile (AASP); the SF36 Quality of Life instrument; and a brief, structured pre-enrolment assessment of attitudes towards yoga. Biomarkers were also assessed. RESULTS: Thirty participants were recruited, with 28 completing the protocol ( Mage=63.5 years). For most variables, there was no significant change in results after the waiting period. Comparing measurements obtained immediately prior to the commencement of the intervention to those taken after completion of eight yoga sessions, significant changes included an increase in the serum dehydroepiandrosterone concentration, decreased total PCL score (and all PCL sub-scales), decreases in all DASS sub-scale scores and significant improvements in PSQI and SF36 scores. No adverse events were reported. CONCLUSIONS: A range of benefits were observed after yoga, consistent with the theoretical construct for the long history of yoga as a strategy to reduce stress and promote well-being.

Emergent Global Contractile Force in Cardiac Tissues.

The heart is a complex organ whose structure and function are intricately linked at multiple length scales. Although several advancements have been achieved in the field of cardiac tissue engineering, current in vitro cardiac tissues do not fully replicate the structure or function necessary for effective cardiac therapy and cardiotoxicity studies. This is partially due to a deficiency in current understandings of cardiac tissue organization's potential downstream effects, such as changes in gene expression levels. We developed a novel (to our knowledge) in vitro tool that can be used to decouple and quantify the contribution of organization and associated downstream effects to tissue function. To do so, cardiac tissue monolayers were designed into a parquet pattern to be organized anisotropically on a local scale, within a parquet tile, and with any desired organization on a global scale. We hypothesized that if the downstream effects were muted, the relationship between developed force and tissue organization could be modeled as a sum of force vectors. With the in vitro experimental platforms of parquet tissues and heart-on-a-chip devices, we were able to prove this hypothesis for both systolic and diastolic stresses. Thus, insight was gained into the relationship between the generated stress and global myofibril organization. Furthermore, it was demonstrated that the developed quantitative tool could be used to estimate the changes in stress production due to downstream effects decoupled from tissue architecture. This has the potential to elucidate properties coupled to tissue architecture, which change force production and pumping function in the diseased heart or stem cell-derived tissues.

Pharmacogenetic associations with long-term response to anti-vascular endothelial growth factor treatment in neovascular AMD patients.

PURPOSE: To investigate the pharmacogenetic associations between the genetic risk variants of age-related macular degeneration (AMD) and long-term outcome after intravitreal anti-vascular endothelial growth factor (VEGF) treatment in Korean neovascular AMD patients. METHODS: This prospective study included 394 treatment-naïve patients (394 eyes) that underwent intravitreal anti-VEGF treatment for neovascular AMD for at least 12 months. Patients were genotyped for 17 single nucleotide polymorphisms within 13 AMD-relevant genes. Initially, patients underwent three monthly injections of intravitreal ranibizumab and were retreated as needed with ranibizumab or bevacizumab. For each candidate polymorphism, genotypic associations with treatment outcome measures at months 12 and 24, including mean change in best-corrected visual acuity (BCVA) from baseline, visual gain of ≥15 letters, mean change in central subfield macular thickness (CSMT) from baseline on spectral domain optical coherence tomography (OCT), presence of fluid on OCT, and mean number of injections, were investigated using logistic or linear regression models with adjustment for non-genetic covariates. RESULTS: At month 24, BCVA improved by 4.5 ± 22.5 letters and CSMT decreased by 69.4 ± 112.6 µm from baseline. Regression analysis with Bonferroni correction showed that the TT genotype for VEGFA rs3025039 was associated with a significantly higher chance of a visual gain of ≥15 letters at month 24 than other genotypes (odds ratio, 4.57; 95% confidence interval, 1.89 - 11.1; corrected p = 0.0434). As for tomographic outcome, the minor allele homozygotes for ARMS2 rs10490924 and HTRA1 rs1100638 (GG genotype for both) were associated with a larger CSMT reduction at month 12 than other genotypes, with borderline significance after Bonferroni correction (118.6 ± 132.7 µm versus 62.7 ± 89.7 µm, corrected p = 0.0656 for rs10490924; 115.7 ± 131.7 µm versus 63.6 ± 89.8 µm, corrected p = 0.0528 for rs11200638). No polymorphism showed a significant association with the number of injections. CONCLUSIONS: In this Korean neovascular AMD cohort, treatment outcome after anti-VEGF was found to differ by the genotypes of VEGFA rs3025039, ARMS2 rs10490924, and HTRA1 rs11200638. Given more evidence of pharmacogenetic associations with the anti-VEGF agent, individualized therapeutic approaches based on genetic background could lead to optimal treatment in neovascular AMD.

Effects of vercirnon on the activity of CYP3A4, CYP2C19 and CYP2C8 enzymes and BCRP and OATP1B1 transporters using probe substrates.

PURPOSE: Vercirnon is a CCR9 chemokine receptor antagonist being developed for the treatment of Crohn's disease. As a variety of concomitant medications are often required for the treatment of Crohn's disease, it is important to characterise the drug interaction profile of vercirnon. To confirm the results of previous in vitro inhibition studies, this study assessed the in vivo effect of vercirnon on the activity of cytochrome P450 enzymes (CYP3A4, CYP2C19 and CYP2C8) and drug transport proteins (BCRP and OATP1B1) using probe substrates. METHODS: This was an open-label, single-sequence, repeat-dose study conducted in 24 healthy adult subjects. On days 1-4, subjects received probe substrates (midazolam, pioglitazone, omeprazole and rosuvastatin; in that order), followed by administration of vercirnon 500 mg twice daily (BID) on days 5-14. On days 11-14, in addition to vercirnon 500 mg BID, subjects also received probe substrates as on days 1-4. Blood samples were collected for pharmacokinetic analysis of probe substrates, vercirnon and two of its metabolites. RESULTS: Geometric least-squares mean ratios (90 % confidence interval) of area under the concentration-time curve from time zero to infinity for probe administered with vercirnon (test) compared with probe alone (reference) for midazolam, pioglitazone, omeprazole and rosuvastatin were 0.92 (0.85, 0.99), 1.01 (0.95, 1.07), 0.99 (0.76,1.31) and 0.98 (0.88, 1.09), respectively. CONCLUSIONS: Co-administration of probe substrates midazolam, pioglitazone, omeprazole, and rosuvastatin following repeat dosing of vercirnon 500 mg BID demonstrated vercirnon had no clinically significant effect on CYP3A4, CYP2C8, CYP2C19 enzyme activity or BCRP or OATP1B1 transporter activity.

Genetic factors associated with response to intravitreal ranibizumab in Korean patients with neovascular age-related macular degeneration.

PURPOSE: To investigate the association between genetic risk variants for age-related macular degeneration (AMD) and response to intravitreal ranibizumab in Korean patients with neovascular AMD. METHODS: This prospective study included 273 treatment-naive patients (273 eyes) who underwent 5 monthly injections (Months 0, 1, 2, 3, and 4) of intravitreal ranibizumab for neovascular AMD. Patients were genotyped for 23 single-nucleotide polymorphisms within 12 AMD-relevant genes. For each polymorphism, genotypic association with good response at Month 5, predetermined as visual improvement of ≥ 8 Early Treatment Diabetic Retinopathy Study letters from baseline, was investigated with logistic regression analysis adjusted for age, gender, smoking, baseline Early Treatment Diabetic Retinopathy Study letter, central retinal thickness, lesion area, and type of choroidal neovascularization. RESULTS: At Month 5, visual acuity improved by 9.1 ± 17.6 letters from baseline, and 136 patients (49.8%) were classified as good responders. In logistic regression, no tested polymorphism showed statistically significant association with favorable visual outcome at Month 5. When unadjusted for multiple tests, AA genotype for VEGF rs699947 had an increased chance of good response compared with other genotypes (odds ratio, 3.61; 95% confidence interval, 1.42-9.18; P = 0.0071). CONCLUSION: In this Korean neovascular AMD cohort, there was no statistically significant effect of genotype on early visual outcome after ranibizumab treatment.

Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells.

RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

Topiramate in combat-related posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that is common among combat veterans and may lead to very poor sleep and disturbing nightmares. OBJECTIVE: To examine the safety and effectiveness of topiramate as add-on therapy for the management of combat-related PTSD and to examine the effects of topiramate on sleep and alcohol consumption. METHODS: We conducted an 8-week open-label pilot study of topiramate for male combat veterans (N = 43) with PTSD, with analysis of veterans who completed the protocol. Psychometric, sleep, and alcohol consumption assessments were conducted at baseline and at week 8. RESULTS: Twenty-nine subjects completed the 8-week study. Significant reductions in Clinician Administered PTSD Scale scores were observed at the 8-week endpoint (from 86.3 +/- 21.1 to 67.1 +/- 25.1; p < 0.01). Decreases were seen in both Stanford Sleepiness Scale scores (from 10.5 +/- 0.72 to 9.0 +/- 0.58; p = 0.08) and Mississippi PTSD scores (from 120.4 +/- 6.5 to 111.5 +/- 20.9; p = 0.08), but the extent of the changes did not attain statistical significance for either scale. There was a significant reduction in the proportion of patients with nightmares (from 100% to 62%; p < 0.001) and patients who experienced anxiety that interfered with falling asleep (from 90% to 62%; p < 0.05). The proportion of patients with high-risk drinking patterns also decreased (from 31% to 14%). Two serious adverse events were reported during the study: an increase in low back pain and an episode of acute confusion. CONCLUSIONS: When used in addition to other empiric therapy, topiramate may be effective at reducing general symptoms of combat-related PTSD and reducing high-risk alcohol intake and nightmares. Further randomized controlled trials of topiramate for the treatment of combat-related PTSD are warranted.

Replication study of the insulin receptor gene in migraine with aura.

We performed the first replication study for the reported association of the insulin receptor gene (INSR) with migraine with aura (MA). Two of 35 SNPs (rs1052371 and rs2860174) reached borderline significance (best uncorrected allelic p value of 0.052 for rs2860174) in stage 1 of our study (270 MA patients, 280 controls). As rs2860174 was 1 of the 5 SNPs with prior evidence of association, we also genotyped this SNP in our stage 2 sample (679 MA patients, 368 controls), and it was nonsignificant (allelic p value 0.478). The combined analysis of our samples showed just a nonsignificant trend for rs2860174 (p=0.1). However, the joint analysis of our study and the initial study reporting an association-including 1278 Caucasian MA patients and 1337 Caucasian controls altogether-displayed a significant allelic p value of 0.005. In conclusion, further association studies for rs2860174 with even larger numbers of individuals are required to exclude or confirm definitely a small effect of this SNP on migraine susceptibility.

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data.

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

Dupuytren's and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene.

Dupuytren's disease (palmar fibromatosis) involves nodules in fascia of the hand that leads to flexion contractures. Ledderhose disease (plantar fibromatosis) is similar with nodules of the foot. While clinical aspects are well-described, genetic mechanisms are unknown. We report a family with cardiac disease due to a heterozygous LMNA mutation (c.736C>T, p.Gln246Stop) with palmar/plantar fibromatosis and investigate the hypothesis that a second rare DNA variant increases the risk for fibrotic disease in LMNA mutation carriers. The proband and six family members were evaluated for the cardiac and hand/feet phenotypes and tested for the LMNA mutation. Fibroblast RNA studies revealed monoallelic expression of the normal LMNA allele and reduced lamin A/C mRNAs consistent with LMNA haploinsufficiency. A novel, heterozygous missense variant (c.230T>C, p.Val77Ala) in the Asteroid Homolog 1 (ASTE1) gene was identified as a potential risk factor in fibrotic disease using exome sequencing and family studies of five family members: four LMNA mutation carriers with fibromatosis and one individual without the LMNA mutation and no fibromatosis. With a possible role in epidermal growth factor receptor signaling, ASTE1 may contribute to the increased risk for palmar/plantar fibromatosis in patients with Lamin A/C haploinsufficiency.

Age of heart disease presentation and dysmorphic nuclei in patients with LMNA mutations.

Nuclear shape defects are a distinguishing characteristic in laminopathies, cancers, and other pathologies. Correlating these defects to the symptoms, mechanisms, and progression of disease requires unbiased, quantitative, and high-throughput means of quantifying nuclear morphology. To accomplish this, we developed a method of automatically segmenting fluorescently stained nuclei in 2D microscopy images and then classifying them as normal or dysmorphic based on three geometric features of the nucleus using a package of Matlab codes. As a test case, cultured skin-fibroblast nuclei of individuals possessing LMNA splice-site mutation (c.357-2A>G), LMNA nonsense mutation (c.736 C>T, pQ246X) in exon 4, LMNA missense mutation (c.1003C>T, pR335W) in exon 6, Hutchinson-Gilford Progeria Syndrome, and no LMNA mutations were analyzed. For each cell type, the percentage of dysmorphic nuclei, and other morphological features such as average nuclear area and average eccentricity were obtained. Compared to blind observers, our procedure implemented in Matlab codes possessed similar accuracy to manual counting of dysmorphic nuclei while being significantly more consistent. The automatic quantification of nuclear defects revealed a correlation between in vitro results and age of patients for initial symptom onset. Our results demonstrate the method's utility in experimental studies of diseases affecting nuclear shape through automated, unbiased, and accurate identification of dysmorphic nuclei.

Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

A phenome-wide association study of variants in genes in the Th17 and IL-17 pathway was performed using self-reported phenotypes and genetic data from 521,000 research participants of 23andMe. Results replicated known associations with similar effect sizes for autoimmune traits illustrating self-reported traits can be a surrogate for clinically assessed conditions. Novel associations controlling for a false discovery rate of 5% included the association of the variant encoding p.Ile684Ser in TYK2 with increased risk of tonsillectomy, strep throat occurrences and teen acne, the variant encoding p.Arg381Gln in IL23R with a decrease in dandruff frequency, the variant encoding p.Asp10Asn in TRAF3IP2 with risk of male-pattern balding, and the RORC regulatory variant (rs4845604) with protection from allergies. This approach enabled rapid assessment of association with a wide variety of traits and investigation of traits with limited reported associations to overlay meaningful phenotypic context on the range of conditions being considered for drugs targeting this pathway.

Exome Sequencing Identifies a Novel LMNA Splice-Site Mutation and Multigenic Heterozygosity of Potential Modifiers in a Family with Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death.

The goals are to understand the primary genetic mechanisms that cause Sick Sinus Syndrome and to identify potential modifiers that may result in intrafamilial variability within a multigenerational family. The proband is a 63-year-old male with a family history of individuals (>10) with sinus node dysfunction, ventricular arrhythmia, cardiomyopathy, heart failure, and sudden death. We used exome sequencing of a single individual to identify a novel LMNA mutation and demonstrated the importance of Sanger validation and family studies when evaluating candidates. After initial single-gene studies were negative, we conducted exome sequencing for the proband which produced 9 gigabases of sequencing data. Bioinformatics analysis showed 94% of the reads mapped to the reference and identified 128,563 unique variants with 108,795 (85%) located in 16,319 genes of 19,056 target genes. We discovered multiple variants in known arrhythmia, cardiomyopathy, or ion channel associated genes that may serve as potential modifiers in disease expression. To identify candidate mutations, we focused on ~2,000 variants located in 237 genes of 283 known arrhythmia, cardiomyopathy, or ion channel associated genes. We filtered the candidates to 41 variants in 33 genes using zygosity, protein impact, database searches, and clinical association. Only 21 of 41 (51%) variants were validated by Sanger sequencing. We selected nine confirmed variants with minor allele frequencies <1% for family studies. The results identified LMNA c.357-2A>G, a novel heterozygous splice-site mutation as the primary mutation with rare or novel variants in HCN4, MYBPC3, PKP4, TMPO, TTN, DMPK and KCNJ10 as potential modifiers and a mechanism consistent with haploinsufficiency.

Detection of genotyping errors by Hardy-Weinberg equilibrium testing.

Genotyping data sets may contain errors that, in some instances, lead to false conclusions. Deviation from Hardy-Weinberg equilibrium (HWE) in random samples may be indicative of problematic assays. This study has analysed 107,000 genotypes generated by TaqMan, RFLP, sequencing or mass spectrometric methods from 443 single-nucleotide polymorphisms (SNPs). These SNPs are distributed both within genes and in intergenic regions. Genotype distributions for 36 out of 313 assays (11.5%) whose minor allele frequencies were >0.05 deviated from HWE (P<0.05). Some of the possible reasons for this deviation were explored: assays for five SNPs proved nonspecific, and genotyping errors were identified in 21 SNPs. For the remaining 10 SNPs, no reasons for deviation from HWE were identified. We demonstrate the successful identification of a proportion of nonspecific assays, and assays harbouring genotyping error. Consequently, our current high-throughput genotyping system incorporates tests for both assay specificity and deviation from HWE, to minimise the genotype error rate and therefore improve data quality.

Pharmacogenetics in diverse ethnic populations--implications for drug discovery and development.

It is widely acknowledged that the vast quantities of data now publicly available as a result of the human genome initiative have the potential to revolutionize the pharmaceutical industry. More tangibly to the drug development business, the dawn of the pharmacogenetics era has the potential to impact not only the discovery of new medicines but also the safety and efficacy of pharmaceutical agents. Coincident with these scientific advances is the emergence of new markets for pharmaceutical agents. Japan, which represents the world's second biggest market, is a good example. With the ICH E5 agreement in 1998 and a rapid change in the drug registration process in Japan, there are increasing opportunities to improve access to more medicines in all parts of the world. However, it is increasingly clear that significant genetic variation still exists between populations, with a host of data on interethnic variation in drug metabolizing enzyme and drug transporter activity. Evidence suggesting that this genetic variation may play an important role in defining some of the interethnic variation in drug response to currently marketed compounds is reviewed here, and future possibilities of using such information to better streamline the drug development process are discussed.

The UK national evaluation of the development and impact of Early Intervention Services (the National EDEN studies): study rationale, design and baseline characteristics.

AIMS: National EDEN aims to evaluate the implementation and impact on key outcomes of somewhat differently configured Early Intervention Services (EIS) across sites in England and to develop a model of variance in patient outcomes that includes key variables of duration of untreated psychosis (DUP), fidelity to the EIS model and service engagement. The cohort is being followed up for two further years as patients are discharged, to observe the stability of change and the impact of the discharge settings. METHODS: A longitudinal cohort study of patients with a first episode of a psychosis, managed by EIS in six services across England. Patients are followed up 12 months after inception, then up to 2 years following discharge. Measures of DUP, psychosis, social functioning and relapse were taken. User and carer experience of EIS were monitored over time; as was the fidelity of each EIS to national guidelines. Service use is costed for a health economic evaluation. RESULTS: 1027 people consented to the study of which 75% were successfully followed up at 12 months, with almost 100% data on treatment, relapse and recovery and service use. CONCLUSIONS: National EDEN is the largest cohort study of young people with psychosis receiving care under EIS. It will be able definitively to indicate whether this major investment in the United Kingdom in EI is achieving meaningful change for its users in practice and provide indications concerning who does well under this approach and who does not, and the long-term stability of any improvements.

Predictive models of choroidal neovascularization and geographic atrophy incidence applied to clinical trial design.

PURPOSE: To develop comprehensive predictive models for choroidal neovascularization (CNV) and geographic atrophy (GA) incidence within 3 years that can be applied realistically to clinical practice. DESIGN: Retrospective evaluation of data from a longitudinal study to develop and validate predictive models of CNV and GA. METHODS: The predictive performance of clinical, environmental, demographic, and genetic risk factors was explored in regression models, using data from both eyes of 2011 subjects from the Age-Related Eye Disease Study (AREDS). The performance of predictive models was compared using 10-fold cross-validated receiver operating characteristic curves in the training data, followed by comparisons in an independent validation dataset (1410 AREDS subjects). Bayesian trial simulations were used to compare the usefulness of predictive models to screen patients for inclusion in prevention clinical trials. RESULTS: Logistic regression models that included clinical, demographic, and environmental factors had better predictive performance for 3-year CNV and GA incidence (area under the receiver operating characteristic curve of 0.87 and 0.89, respectively), compared with simple clinical criteria (AREDS simplified severity scale). Although genetic markers were associated significantly with 3-year CNV (CFH: Y402H; ARMS2: A69S) and GA incidence (CFH: Y402H), the inclusion of genetic factors in the models provided only marginal improvements in predictive performance. CONCLUSIONS: The logistic regression models combine good predictive performance with greater flexibility to optimize clinical trial design compared with simple clinical models (AREDS simplified severity scale). The benefit of including genetic factors to screen patients for recruitment to CNV prevention studies is marginal and is dependent on individual clinical trial economics.