Validating and Updating the OHTS-EGPS Model Predicting 5-year Glaucoma Risk among Ocular Hypertension Patients Using Electronic Records

Objective: To validate and update the Ocular Hypertension Treatment Study-European Glaucoma Prevention Study (OHTS-EGPS) model predicting risk of conversion from ocular hypertension (OHT) to glaucoma using electronic medical records (EMR). // Design: Evaluation and update of a risk prediction algorithm using EMRs and linked visual field (VF) tests. // Participants: Newly diagnosed OHT patients attending hospital glaucoma services in England. Inclusion criteria are as follows: intraocular pressure (IOP) 22 to 32 mmHg (either eye); normal baseline VF test, defined as Glaucoma Hemifield Test (GHT) “within normal range” in a reliable VF test; at least 2 VF tests in total; no significant ocular comorbidities. // Methods: Risk factors are as follows: age, ethnicity, sex, IOP, vertical cup-to-disc ratio, central corneal thickness, VF pattern standard deviation, family history of glaucoma, systemic hypertension, diabetes mellitus, and glaucoma treatment. Glaucoma conversion was defined as 2 consecutive and reliable VF tests with GHT “outside normal limits” and/or need for glaucoma surgery. For validation, the OHTS-EGPS model was applied to predict a patient’s risk of developing glaucoma in 5 years. In the updating stage, the OHTS model was refitted by re-estimating the baseline hazard and regression coefficients. The updated model was cross-validated and several variants were explored. // Main Outcome Measures: Measures of discriminative ability (c-index) and calibration (calibration slope) were calculated and pooled across hospitals using random effects meta-analysis. // Results: From a total of 138 461 patients from 10 hospital glaucoma services in England, 9030 patients with OHT fitted the inclusion criteria. A total of 1530 (16.9%) patients converted to glaucoma during this follow-up period. The OHTS-EGPS model provided a pooled c-index of 0.61 (95% confidence interval: 0.60–0.63), ranging from 0.55 to 0.67 between hospitals. The pooled calibration slope was 0.45 (0.38–0.51), ranging from 0.25 to 0.64 among hospitals. The overall refitted model performed better than the OHTS-EGPS model, with a pooled c-index of 0.67 (0.65–0.69), ranging from 0.65 to 0.75 between hospitals. // Conclusions: We performed an external validation of the OHTS-EGPS model in a large English population. Refitting the model achieved modest improvements in performance. Given the poor performance of the OHTS-EGPS model in our population, one should use caution in its application to populations that differ from those in the OHTS and EGPS. // Financial Disclosure(s) Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Validating and updating the OHTS-EGPS model predicting 5-year glaucoma risk among ocular hypertension patients using electronic records

Objective: To validate and update the Ocular Hypertension Treatment Study-European Glaucoma Prevention Study (OHTS-EGPS) model predicting risk of conversion from ocular hypertension (OHT) to glaucoma using electronic medical records (EMR). Design: Evaluation and update of a risk prediction algorithm using EMRs and linked visual field (VF) tests. Participants: Newly diagnosed OHT patients attending hospital glaucoma services in England. Inclusion criteria are as follows: intraocular pressure (IOP) 22 to 32 mmHg (either eye); normal baseline VF test, defined as Glaucoma Hemifield Test (GHT) “within normal range” in a reliable VF test; at least 2 VF tests in total; no significant ocular comorbidities. Methods: Risk factors are as follows: age, ethnicity, sex, IOP, vertical cup-to-disc ratio, central corneal thickness, VF pattern standard deviation, family history of glaucoma, systemic hypertension, diabetes mellitus, and glaucoma treatment. Glaucoma conversion was defined as 2 consecutive and reliable VF tests with GHT “outside normal limits” and/or need for glaucoma surgery. For validation, the OHTS-EGPS model was applied to predict a patient’s risk of developing glaucoma in 5 years. In the updating stage, the OHTS model was refitted by re-estimating the baseline hazard and regression coefficients. The updated model was cross-validated and several variants were explored. Main Outcome Measures: Measures of discriminative ability (c-index) and calibration (calibration slope) were calculated and pooled across hospitals using random effects meta-analysis. Results: From a total of 138 461 patients from 10 hospital glaucoma services in England, 9030 patients with OHT fitted the inclusion criteria. A total of 1530 (16.9%) patients converted to glaucoma during this follow-up period. The OHTS-EGPS model provided a pooled c-index of 0.61 (95% confidence interval: 0.60–0.63), ranging from 0.55 to 0.67 between hospitals. The pooled calibration slope was 0.45 (0.38–0.51), ranging from 0.25 to 0.64 among hospitals. The overall refitted model performed better than the OHTS-EGPS model, with a pooled c-index of 0.67 (0.65–0.69), ranging from 0.65 to 0.75 between hospitals. Conclusions: We performed an external validation of the OHTS-EGPS model in a large English population. Refitting the model achieved modest improvements in performance. Given the poor performance of the OHTS-EGPS model in our population, one should use caution in its application to populations that differ from those in the OHTS and EGPS

Validating and updating the OHTS-EGPS model predicting 5-year glaucoma risk among ocular hypertension patients using electronic records.

To validate and update the OHTS-EGPS model predicting risk of conversion from OHT to glaucoma using electronic medical records (EMR). Evaluation and update of a risk prediction algorithm using EMRs and linked visual field (VF) tests. Newly diagnosed OHT patients attending hospital glaucoma services in England. IOP 22-32 mmHg (either eye); normal baseline VF test, defined as Glaucoma Hemifield Test (GHT) 'within normal range' in a reliable VF test; at least two VF tests in total; no significant ocular co-morbidities. Risk factors: age, ethnicity, sex, IOP, vertical cup-to-disc ratio, central corneal thickness, VF pattern standard deviation, family history of glaucoma, systemic hypertension, diabetes mellitus, glaucoma treatment. Glaucoma conversion was defined as two consecutive and reliable VF tests with GHT 'outside normal limits' and/or need for glaucoma surgery. For validation, the OHTS-EGPS model was applied to predict a patient's risk of developing glaucoma in 5 years. In the updating stage, the OHTS-model was re-fitted by re-estimating the baseline hazard and regression coefficients. The updated model was cross-validated and several variants were explored. Measures of discriminative ability (c-index) and calibration (calibration slope) were calculated and pooled across hospitals using random effects meta-analysis. From a total of 138,461 patients from ten hospital glaucoma services in England 9030 patients with OHT fitted the inclusion criteria. A total of 1530 (16.9%) patients converted to glaucoma during this follow-up period. The OHTS-EGPS model provided a pooled c-index of 0.61 (95% confidence interval: 0.60, 0.63), ranging from 0.55 to 0.67 between hospitals. The pooled calibration slope was 0.45 (0.38, 0.51), ranging from 0.25 to 0.64 among hospitals. The overall re-fitted model performed better than the OHTS-EGPS model, with a pooled c-index of 0.67 (0.65, 0.69), ranging from 0.65 to 0.75 between hospitals. We performed an external validation of the OHTS-EGPS model in a large English population. Re-fitting the model achieved modest improvements in performance. Given the poor performance of the OHTS-EGPS model in our population, one should use caution in its application to populations that differ from those in the OHTS and EGPS. [Abstract copyright: Copyright © 2024. Published by Elsevier Inc.

Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility : a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A > G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 x 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 x 10(-3) and 7.0 x 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 x 10(-3), 4.5 x 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.Peer reviewe

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk : a case-control study

Abstract Introduction We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P trend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P trend = 0.005) but not cases (P trend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P het = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; P trend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; P trend = 0.29). Conclusions To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important

The Risk of Serious Infections Before and After Anti-TNF Therapy in Inflammatory Bowel Disease : A Retrospective Cohort Study

BACKGROUND: Serious infections have been observed in patients with inflammatory bowel disease (IBD) on anti-TNF use-but to what extent these infections are due to anti-TNF or the disease activity per se is hard to disentangle. We aimed to describe how the rates of serious infections change over time both before and after starting anti-TNF in IBD.METHODS: Inflammatory bowel disease patients naïve to anti-TNF treatment were identified at 5 centers participating in the Swedish IBD Quality Register, and their medical records examined in detail. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated.RESULTS: Among 980 patients who started their first anti-TNF therapy between 1999 and 2016, the incidence rate of serious infections was 2.19 (95% CI,1.43-3.36) per 100 person years the year before and 2.11 (95% CI, 1.33-3.34) per 100 person years 1 year after treatment start. This corresponded to an incidence rate ratio 1 year after anti-TNF treatment of 0.97 (95% CI, 0.51-1.84). Compared with before anti-TNF therapy, the incidence of serious infection was significantly decreased more than 1 year after treatment (incidence rate ratio 0.56; 95% CI, 0.33-0.95; P = .03).CONCLUSIONS: In routine clinical practice in Sweden, the incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment

Capturing biologic treatment for IBD in the Swedish Prescribed Drug Register and the Swedish National Patient Register–a validation study [Elektronisk resurs]

Background: It is not known to what extent biologic treatment for IBD is captured in the Swedish Prescribed Drug Register (PDR) and the National Patient Register (NPR). Methods: A cross-sectional study from July 2005 until 2017, comparing data on biologic treatment in the PDR and the NPR with medical records. We assessed the proportion of started treatment episodes in the medical records that were found in the PDR/NPR ever, within +/− one year and within +/− three months; for any biologic drug, per specific drug (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab), by calendar period (2005–2008, 2009–2012, and 2013–2017) and by study center. For adalimumab, we assessed the validity of end of treatment episodes. Results: Medical records of 1361 patients and 2323 treatment episodes with any biologic were reviewed and 80.1% (95% CI: 78.4–81.7) were ever captured in the PDR/NPR in. A time window of +/− one year or +/− three months reduced the sensitivity to 63.3% (95% CI: 61.3–65.3) and 52.6% (95% CI: 50.5–54.6), respectively. The sensitivity was high (>85%) for the prescribed injection drugs adalimumab, golimumab, and ustekinumab for all time windows and for adalimumab end of treatment, while considerably lower for the infusion drugs infliximab and vedolizumab. Conclusions: The PDR and the NPR are reliable data sources on treatment with injection biologics in patients with IBD in Sweden. Infliximab and vedolizumab are poorly captured, why PDR/NPR data should only be used after careful consideration of their limitations or complemented by other data sources, e.g., the disease-specific quality register SWIBREG