Moderate Progressors Research Articles

#2295 Can we detect the evolution of GFR with estimated GFR in patients with ADPKD?

Abstract Background and Aims ADPKD affects about 10% of the patients with CKD. In the disease the formation of cysts replace normal renal parenchyma leading to renal function loss. The evolution of the disease is irregular: some patients lose renal function very fast while others remain stable or have a slow loss. This may have consequences in clinical care. In day-to-day practice, GFR is evaluated by means of formulas, which are algorithms that use creatinine and others markers like age and gender to estimate GFR. However, the accuracy and precision of eGFR in reflecting real GFR in ADPKD is not clear, being this the objective of our study. Method To analyse the capacity of eGFR by creatinine-based formulas in predicting mGFR changes over time. We evaluated patients with ADPKD, who underwent mGFR and eGFR by a group 5 equations at baseline, month 6 and then annually. mGFR was evaluated by the clearance of iohexol using dried blood spots (iohexol-DBS) and eGFR with the following creatinine-based equations: Cockcroft-Gault, aMDRD, CKD-EPI, FAS and EKFC. We calculated renal function decline (GFR decline) using repeated measured with mGFR and eGFR. All subjects have at least 3 repeated evaluations of renal function. The agreement between mGFR and eGFR declines was analysed by the concordance correlation coefficient (CCC). Also, we evaluated the capacity of eGFR decline in detecting diverse degree of GFR decline (a) rapid progressors: mGFR of −5 ml/min/y; (b) moderate progressors: −2 to −5 ml/min/y; (c) stable: > −2 ml/min/y. Results We evaluated 111 (43; 37% men); age: 42 y ± 14, with a 5 ± 1 evaluations of GFR over time (mGFR and eGFR). The average GFR decline was: −2,8 ml/min/year (mGFR); −3,1 (Cockcroft-Gault), −2,9 (aMDRD), −3,0 (CKD-EPI), −2,8 (FAS) and −2,6 (EFKC) According with mGFR decline, 21 patients (19%) were rapid progressors; 46 (41%) moderate progressors and 44 (40%) stable. The agreement between eGFR decline and mGFR decline was poor, reflected by a low CCC: 0.37 (Cockcroft-Gault); 0.76 (aMDRD); 0.80 (CKD-EPI), 0.77 (FAS); 0.81 (EFKC). In general, eGFR decline failed to detect progression of renal function over time. On average, 43% of the rapid progressors, 53% of the moderate progressors and 54% of the stable patients were not detected by any formula, respectively. Finally, a total of 12% and 6% of those stable or moderate progressors were falsely classified as rapid progressors. Conclusion eGFR is not able to reflect properly renal function changes over time in patients with ADPKP in about half of the patients. A relevant number of cases are erroneously considered as rapid progressors or even stable patients. This may have clinical consequences. Whenever possible, mGFR could be considered in this population.

Association between progression of coronary artery calcification and development of kidney failure with replacement therapy: Findings from KNOW-CKD study

Background and aimsHigh coronary artery calcification (CAC) burden is a significant risk factor for adverse cardiovascular and kidney outcomes. However, it is unknown whether changes in the coronary atherosclerotic burden can accompany changes in kidney disease progression. Here, we evaluated the relationship between CAC progression and the risk of kidney failure with replacement therapy (KFRT). MethodsWe analyzed 1173 participants with chronic kidney disease (CKD) G1 to G5 without kidney replacement therapy from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Participants were categorized into three groups according to the change in the CAC score between enrollment and year 4 (non-progressors, ≤0 AU; moderate progressors, 1–199 AU; and severe progressors, ≥200 AU). The primary outcome was the development of KFRT. ResultsDuring a follow-up period of 4690 person-years (median, 4.2 years), the primary outcome occurred in 230 (19.6 %) participants. The incidence of KFRT was 37.6, 54.3, and 80.9 per 1000 person-years in the non-, moderate, and severe progressors, respectively. In the multivariable cause-specific hazard model, the hazard ratios (HRs) for the moderate and severe progressors were 1.71 (95 % confidence interval [CI], 1.02–2.87) and 2.55 (95 % CI, 1.07–6.06), respectively, compared with non-progressors. A different definition of CAC progression with a threshold of 100 AU yielded similar results in a sensitivity analysis. ConclusionsCAC progression is associated with an increased risk of KFRT in patients with CKD. Our findings suggest that coronary atherosclerosis changes increase the risk of CKD progression.

ALSFRS-R decline rate prior to baseline is not useful for stratifying subsequent progression of functional decline

Objective One of the difficulties in developing a novel drug for patients with amyotrophic lateral sclerosis (ALS) is the significant variation in the clinical course. To control this variation, a 12-week run-in period is used in some clinical trials. Based on the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) change during the run-in period, only moderate progressors are selected in some clinical trials. Some reports showed that the ALSFRS-R progression rate was associated with survival. However, it is unclear whether the ALSFRS-R change in the run-in period is a useful prognostic factor of the ALSFRS-R change from baseline. In addition, we explore the inclusion criteria that could control the variability in ALS-function progression without setting a run-in period. Methods We utilized the Japanese and US ALS registry databases (JaCALS and PRO-ACT). Patients were classified into three populations (rapid, moderate, and slow progressors) based on the ALSFRS-R change prior to baseline. We also classified patients into three prognostic populations based on the ALSFRS-R change from baseline. We confirmed whether each of the three populations were matched with their respective three prognostic populations. Results Our data showed that the three groups classified by the ALSFRS-R change during the 12 weeks prior to baseline or by the rate of progression from onset to baseline did not accord with the three prognostic groups. Conclusions Our results showed that the ALSFRS-R change in the run-in period or from onset to baseline is not useful for stratifying subsequent progression of functional decline in clinical trials.

Prognostic enrichment for early-stage Huntington’s disease: An explainable machine learning approach for clinical trial

BackgroundIn Huntington’s disease clinical trials, recruitment and stratification approaches primarily rely on genetic load, cognitive and motor assessment scores. They focus less on in vivo brain imaging markers, which reflect neuropathology well before clinical diagnosis. Machine learning methods offer a degree of sophistication which could significantly improve prognosis and stratification by leveraging multimodal biomarkers from large datasets. Such models specifically tailored to HD gene expansion carriers could further enhance the efficacy of the stratification process. ObjectivesTo improve stratification of Huntington’s disease individuals for clinical trials. MethodsWe used data from 451 gene positive individuals with Huntington’s disease (both premanifest and diagnosed) from previously published cohorts (PREDICT, TRACK, TrackON, and IMAGE). We applied whole-brain parcellation to longitudinal brain scans and measured the rate of lateral ventricular enlargement, over 3 years, which was used as the target variable for our prognostic random forest regression models. The models were trained on various combinations of features at baseline, including genetic load, cognitive and motor assessment score biomarkers, as well as brain imaging-derived features. Furthermore, a simplified stratification model was developed to classify individuals into two homogenous groups (low risk and high risk) based on their anticipated rate of ventricular enlargement. ResultsThe predictive accuracy of the prognostic models substantially improved by integrating brain imaging features alongside genetic load, cognitive and motor biomarkers: a 24 % reduction in the cross-validated mean absolute error, yielding an error of 530 mm3/year. The stratification model had a cross-validated accuracy of 81 % in differentiating between moderate and fast progressors (precision = 83 %, recall = 80 %). ConclusionsThis study validated the effectiveness of machine learning in differentiating between low- and high-risk individuals based on the rate of ventricular enlargement. The models were exclusively trained using features from HD individuals, which offers a more disease-specific, simplified, and accurate approach for prognostic enrichment compared to relying on features extracted from healthy control groups, as done in previous studies. The proposed method has the potential to enhance clinical utility by: i) enabling more targeted recruitment of individuals for clinical trials, ii) improving post-hoc evaluation of individuals, and iii) ultimately leading to better outcomes for individuals through personalized treatment selection.

Risk factors for structural and functional progression of primary open-angle glaucoma in an African ancestry cohort

Background/aimsTo investigate the rates of structural and functional progression of primary open-angle glaucoma in an African ancestry cohort and identify risk factors for progression.MethodsThis retrospective study included 1424 eyes from...

Clustering and prediction of disease progression trajectories in Huntington's disease: An analysis of Enroll-HD data using a machine learning approach.

Huntington's disease (HD) is a rare neurodegenerative disease characterized by cognitive, behavioral and motor symptoms that progressively worsen with time. Cognitive and behavioral signs of HD are generally present in the years prior to a diagnosis; however, manifest HD is typically assessed by genetic confirmation and/or the presence of unequivocal motor symptoms. Nevertheless, there is a large variation in symptom severity and rate of progression among individuals with HD. In this retrospective study, longitudinal natural history of disease progression was modeled in individuals with manifest HD from the global, observational Enroll-HD study (NCT01574053). Unsupervised machine learning (k-means; km3d) was used to jointly model clinical and functional disease measures simultaneously over time, based on one-dimensional clustering concordance such that individuals with manifest HD (N = 4,961) were grouped into three clusters: rapid (Cluster A; 25.3%), moderate (Cluster B; 45.5%) and slow (Cluster C; 29.2%) progressors. Features that were considered predictive of disease trajectory were then identified using a supervised machine learning method (XGBoost). The cytosine adenine guanine-age product score (a product of age and polyglutamine repeat length) at enrollment was the top predicting feature for cluster assignment, followed by years since symptom onset, medical history of apathy, body mass index at enrollment and age at enrollment. These results are useful for understanding factors that affect the global rate of decline in HD. Further work is needed to develop prognostic models of HD progression as these could help clinicians with individualized clinical care planning and disease management.

Identification and prediction of Parkinson’s disease subtypes and progression using machine learning in two cohorts

The clinical manifestations of Parkinson’s disease (PD) are characterized by heterogeneity in age at onset, disease duration, rate of progression, and the constellation of motor versus non-motor features. There is an unmet need for the characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. We used unsupervised and supervised machine learning methods on comprehensive, longitudinal clinical data from the Parkinson’s Disease Progression Marker Initiative (n = 294 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson’s Disease Biomarker Program (n = 263 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate, and fast disease progression. We achieved highly accurate projections of disease progression 5 years after initial diagnosis with an average area under the curve (AUC) of 0.92 (95% CI: 0.95 ± 0.01) for the slower progressing group (PDvec1), 0.87 ± 0.03 for moderate progressors, and 0.95 ± 0.02 for the fast-progressing group (PDvec3). We identified serum neurofilament light as a significant indicator of fast disease progression among other key biomarkers of interest. We replicated these findings in an independent cohort, released the analytical code, and developed models in an open science manner. Our data-driven study provides insights to deconstruct PD heterogeneity. This approach could have immediate implications for clinical trials by improving the detection of significant clinical outcomes. We anticipate that machine learning models will improve patient counseling, clinical trial design, and ultimately individualized patient care.

Rapid initial OCT RNFL thinning is predictive of faster visual field loss during extended follow-up in glaucoma

To investigate the relationship between the rate of retinal nerve fiber layer (RNFL) loss during initial follow-up and the magnitude of associated visual field loss during an extended follow-up period. Retrospective cohort study. A total of 1,150 eyes of 839 glaucoma patients extracted from the Duke Glaucoma Registry. Rates of RNFL loss were obtained from global RNFL thickness values of the first 5 optical coherence tomography (OCT) scans. Rates of visual field loss were assessed using standard automated perimetry mean deviation (SAP MD) during the entire follow-up period. Joint longitudinal mixed effects models were used to estimate rates of change. Eyes were categorized as fast, moderate or slow progressors based on rates of RNFL loss, with cutoffs of ≤-2 µm/year, -2 to -1 µm/year and ≥-1 µm/year, respectively. Univariable and multivariable regressions were completed to identify significant predictors of SAP MD loss. The rate of RNFL change was -0.76±0.85 µm/y during initial follow-up, which occurred over 3.7±1.5 years. 765 (66%) eyes were slow, 328 (29%) moderate, and 57 (5%) fast progressors, with rates of RNFL thinning of -0.36±0.54 µm/year, -1.34±0.25 µm/year, and -2.87±1.39 µm/year respectively. The rates of SAP MD loss among slow, moderate, and fast OCT progressors were -0.16±0.35 dB/y, -0.32±0.43 dB/y, and -0.71±0.65 dB/y respectively over the extended follow-up period of 6.1±1.9 years (P<0.001). Age, OCT progressor group, and concurrent SAP rate were all significantly associated with the overall rate of SAP MD loss in a multivariable model (all P<0.001). Rapid RNFL thinning during an initial follow-up period was predictive of concurrent and subsequent rates of visual field decline over an extended period.

Categorisation of myopia progression by change in refractive error and axial elongation and their impact on benefit of myopia control using orthokeratology.

AimsTo compare the value of pre-treatment axial elongation (AE) and changes in refractive sphere (M change) for predicting the success in orthokeratology (ortho-k), in order to better identify suitable candidates for myopia control.MethodsThis study further analysed the data of 66 subjects receiving 7-month ortho-k treatment, following a 7-month observation period, during which single-vision spectacles were worn. Rate of myopia progression was determined by AE and M change and subjects categorised as slow, moderate, or rapid progressors based on these changes. Outcomes of myopia control, based on the AE reduction after ortho-k, were classified as ‘ineffectual’, ‘clinically insignificant’, or ‘beneficial’.ResultsOf the 20 subjects, initially categorised as slow by AE and, of whom 95% were similarly categorised by M change, none benefitted from ortho-k. In contrast, of the 22 subjects with moderate AE, 77% and 23% displaying slow and moderate M change, respectively, the majority (73%) benefitted from ortho-k lens wear. The 24 subjects with rapid AE were poorly identified by M change, with only 21% correctly categorised. The vast majority of rapid progressors showed significant benefit after ortho-k.ConclusionProgression of AE is a good indicator of subsequent success of ortho-k treatment. Delaying commencement of therapy is prudent for children with slow progression as results indicate that they would be unlikely to benefit from this intervention. As change in refractive error frequently underestimates rapid progression of AE, its value for identifying appropriate candidates for myopia control is poor.

Brief Report: CYP27B1 rs10877012 T Allele Was Linked to Non-AIDS Progression in ART-Naïve HIV-Infected Patients: A Retrospective Study.

HIV/AIDS progression is linked to vitamin D, which is regulated by several key cytochromes P450 (CYP). Single nucleotide polymorphisms (SNPs) in CYP genes influence vitamin D metabolism and serum levels. The objective of this study was to evaluate the association between CYP SNPs and the clinical AIDS progression in antiretroviral treatment (ART)-naïve HIV-infected patients. We performed a retrospective study in 661 ART-naïve HIV-infected patients who were stratified by their AIDS progression pattern [181 long-term nonprogressors (LTNPs), 332 moderate progressors, and 148 rapid progressors (RPs)]. Four CYP SNPs (CYP2R1 rs10500804, CYP2R1 rs1993116, CYP27B1 rs10877012, and CYP24A1 rs6013897) were genotyped using Agena Bioscience's MassARRAY platform. Correction for multiple testing was performed using the false discovery rate (Benjamini-Hochberg procedure). The adjusted regression showed a significant association only for CYP27B1 rs10877012 SNP. When analyzing all HIV patients, the rs10877012 T allele was protective against AIDS progression (ordinal outcome) under the dominant [adjusted odds ratio (aOR) = 0.69; P = 0.021) and additive (aOR) = 0.75; P = 0.025] inheritance models. When analyzing LTNPs versus RPs, the rs10877012 T allele also showed a significant protective association under the dominant (aOR = 0.45; P = 0.004) and additive (aOR = 0.54; P = 0.008) inheritance models. P values remained significant after correcting by multiple comparisons only for the comparison of LTNPs versus RPs (extreme phenotypes). The CYP27B1 rs10877012 T allele was linked to non-AIDS progression in ART-naïve HIV-infected patients. The rs10877012 SNP seems to have an impact on the clinical AIDS progression, possibly modifying vitamin D levels, which could be relevant for the pathogenesis of HIV infection.

Model-based meta-analysis of individual International Prostate Symptom Score trajectories in patients with benign prostatic hyperplasia with moderate or severe symptoms.

AimsInternational Prostate Symptom Score (IPSS) is a marker of lower urinary tract symptoms (LUTS) deterioration or improvement in benign prostate hyperplasia (BPH). Whereas changes in IPSS relative to baseline have been used as endpoints in clinical trials, little attention has been given to the time course of symptoms. The current investigation aimed to develop a drug‐disease model to describe individual IPSS trajectories in moderate and severe BPH patients.MethodsA model‐based meta‐analytical approach was used including data from 10 238 patients enrolled into Phase III and IV studies receiving placebo, tamsulosin, dutasteride or combination therapy over a period of up to 4 years. Model predictive performance was assessed using statistical and graphical criteria. Subsequently, simulations were performed to illustrate the implications of treatment with drugs showing symptomatic and disease‐modifying properties in patients with varying disease progression rates.ResultsImprovement and worsening of IPSS could be characterized by a model including a sigmoid function which disentangles drug effects from placebo and varying disease progression rates on IPSS. Mean estimate (95% confidence intervals) for the disease progression rate was 0.319 (0.271–0.411) month−1. Treatment effect on IPSS (DELTA) was found to be 0.0605, 0.0139 and 0.0310 month−1 for placebo, tamsulosin and combination therapy, respectively. In addition, it appears that individual trajectories can be clustered together into different phenotypes describing the underlying disease progression rate (i.e. slow, moderate and fast progressors).ConclusionsThe availability of a drug‐disease model enables the evaluation of interindividual differences in disease progression rate, deterioration of symptoms and treatment effects on LUTS/BPH.

DBP rs16846876 and rs12512631 polymorphisms are associated with progression to AIDS na\xefve HIV-infected patients: a retrospective study

BackgroundMost of the circulating Vitamin D (VitD) is transported bound to vitamin D-binding protein (DBP), and several DBP single nucleotide polymorphisms (SNPs) have been related to circulating VitD concentration and disease. In this study, we evaluated the association among DBP SNPs and AIDS progression in antiretroviral treatment (ART)-naïve-HIV-infected patients.MethodsWe performed a retrospective study in 667 patients who were classified according to their pattern of AIDS progression (183 long-term non-progressors (LTNPs), 334 moderate progressors (MPs), and 150 rapid progressors (RPs)) and 113 healthy blood donors (HIV, HCV, and HBV negative subjects). We genotyped seven DBP SNPs (rs16846876, rs12512631, rs2070741, rs2282679, rs7041, rs1155563, rs2298849) using Agena Bioscience’s MassARRAY platform. The genetic association was evaluated by Generalized Linear Models adjusted by age at the moment of HIV diagnosis, gender, risk group, and VDR rs2228570 SNP. Multiple testing correction was performed by the false discovery rate (Benjamini and Hochberg procedure; q-value).ResultsAll SNPs were in HWE (p > 0.05) and had similar genotypic frequencies for DBP SNPs in healthy-controls and HIV-infected patients. In unadjusted GLMs, we only found significant association with AIDS progression in rs16846876 and rs12512631 SNPs. In adjusted GLMs, DBP rs16846876 SNP showed significant association under the recessive inheritance model [LTNPs vs. RPs (adjusted odds ratio (aOR) = 3.53; q-value = 0.044) and LTNPs vs. MPs (aOR = 3.28; q-value = 0.030)] and codominant [LTNPs vs. RPs (aOR = 4.92; q-value = 0.030) and LTNPs vs. MPs (aOR = 3.15; q-value = 0.030)]. Also, we found DBP rs12512631 SNP showed significant association in the inheritance model dominant [LTNPs vs. RPs (aOR = 0.49; q-value = 0.031) and LTNPs vs. MPs (aOR = 0.6; q-value = 0.047)], additive [LTNPs vs. RPs (aOR = 0.61; q-value = 0.031)], overdominant [LTNPs vs. MPs (aOR = 0.55; q-value = 0.032)], and codominant [LTNPs vs. RPs (aOR = 0.52; q-value = 0.036) and LTNPs vs. MPs (aOR = 0.55; q-value = 0.032)]. Additionally, we found a significant association between DBP haplotypes (composed by rs16846876 and rs12512631) and AIDS progression (LTNPs vs RPs): DBP haplotype AC (aOR = 0.63; q-value = 0.028) and the DBP haplotype TT (aOR = 1.64; q-value = 0.028).ConclusionsDBP rs16846876 and rs12512631 SNPs are related to the patterns of clinical AIDS progression (LTNP, MP, and RP) in ART-naïve HIV-infected patients. Our findings provide new knowledge about AIDS progression that may be relevant to understanding the pathogenesis of HIV infection.

211-OR: Analysis of Longitudinal Autoantibody Profiles and the Progression Rates to Type 1 Diabetes

Clinical type 1 diabetes (T1D) is preceded by asymptomatic islet-autoimmunity (IA) with presence of islet autoantibodies (AAb). However, both AAb profiles (clusters) during IA phase and progression rate to T1D are heterogeneous. It is unclear if AAb profiles affect the progression to T1D similarly in different countries. We analyzed data from 3 prospective birth cohorts, DAISY (U.S.), DiPiS (Sweden), and DIPP (Finland), to address this question. We developed a similarity algorithm that considers subject-level temporal IA profiles (based on 4 AAbs - IAA, GADA, IA2A, and ZnT8A positivity or negativity), age at which AAb developed, and imbalance in AAb positivity by weighting positive AAb matches higher than negative ones. Using this subject-level similarity measure, we performed hierarchical clustering of AAb positive subjects having at least 3 visits. We used a log-rank test to identify the number of clusters in 1125 DIPP subjects (329 T1D cases), 309 DAISY subjects (70 cases), and 226 DiPiS subjects (33 cases). Each dataset was individually clustered. We identified three clusters in each dataset associated with different rate of progression from seroconversion to T1D - slow progressors (SP), moderate progressors (MP) and fast progressors (FP). These were distributed as follows: DIPP (654 SP with 3% 10-year T1D risk, 356 MP with 60% risk, 115 FP with 96% risk); DAISY (215 SP with 6% 10-year risk, 92 MP with 62% risk, 2 FP with 100% risk); and DiPiS (160 SP with 3% 10-year risk, 62 MP with 58% risk, 4 FP with 100% risk). Finally, we tested the generalizability of the clusters by 1) learning a clustering from one data set “learned clusters,” 2) classifying subjects from another (independent) data set with the “learned clusters,” and 3) measuring how often the subjects were assigned to the same cluster (SP, MP, FP) as the “internal” clustering. The average accuracy of cluster transfer was high (mean = 87.9%, sd = 1.1%) suggesting that the IA profile predicts progression rate to T1D independently of the population. Disclosure M. Ghalwash: None. V. Anand: None. B. Liu: None. E. Koski: None. K. Ng: None. J.L. Dunne: None. M. Lundgren: None. M. Rewers: None. R. Veijola: None. Funding JDRF

VDR rs2228570 Polymorphism Is Related to Non-Progression to AIDS in Antiretroviral Therapy Naïve HIV-Infected Patients.

Background: Vitamin D is a fundamental regulator of host defenses by activating genes related to innate and adaptive immunity. In this study, we analyzed the association among single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene, with clinical patterns of AIDS progression in antiretroviral treatment (ART)-naïve HIV-infected patients. Methods: We conducted a retrospective study in 667 HIV-infected patients, who were classified within three groups according to their AIDS progression pattern (183 long-term non-progressors (LTNPs), 334 moderate progressors (MPs), and 150 rapid progressors (RPs)). Five VDR SNPs (rs11568820, rs4516035, rs2228570, rs1544410, and rs7975232) were genotyped using Agena Bioscience’s MassARRAY platform. Results: Significant association results were found for rs2228570. Within all HIV patients, the presence of T allele at VDR rs2228570 SNP was protective against AIDS progression (ordinal outcome) under additive (adjusted odds ratio (aOR) = 0.75; p = 0.009), dominant (aOR = 0.69; p = 0.015), and codominant (aOR = 0.56; p = 0.017) inheritance models. In addition, the same allele was protective under additive and codominant inheritance models when we compared with LTNPs vs. RPs [aOR = 0.64 (p = 0.019) and aOR = 0.37 (p = 0.018), respectively] and when we compared MPs vs. RPs [aOR = 0.72 (p = 0.035) and aOR = 0.45 (p = 0.028), respectively]. Conclusions: The VDR rs2228570 T allele was related to a lower AIDS progression pattern in ART-naïve HIV-infected patients. These findings expand upon the knowledge about HIV pathogenesis in untreated HIV-infected patients with different clinical outcomes.

Predictors of slow progression to diabetes in children with multiple islet autoantibodies

Although most children with multiple islet autoantibodies develop type 1 diabetes, rate of progression is highly variable. The goal of this study was to explore potential factors involved in rate of progression to diabetes in children with multiple islet autoantibodies. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 118 children with multiple islet autoantibodies for progression to diabetes. After excluding 27 children currently diabetes-free but followed for <10 years, the study population was grouped into: rapid progressors (N = 39) who developed diabetes in <5 years; moderate progressors (N = 25), diagnosed with diabetes within 5–10 years; and slow progressors (N = 27), diabetes-free for >10 years. Islet autoimmunity appeared at 4.0 ± 3.5, 3.2 ± 1.8 and 5.8 ± 3.1 years of age in rapid, moderate and slow progressors, respectively (p = 0.006). Insulin autoantibody levels were lower in slow progressors compared to moderate and rapid progressors. The groups did not differ by gender, ethnicity, family history, susceptibility HLA and non-HLA genes. The rate of development of individual islet autoantibodies including mIAA, GADA, IA-2A and ZnT8A were all slower in the slow versus moderate/rapid progressors. In multivariate analyses, older age at seroconversion and lower initial mIAA levels independently predicted slower progression to diabetes. Later onset of islet autoimmunity and lower autoantibody levels predicted slower progression to diabetes among children with multiple islet autoantibodies. These factors may need to be considered in the design of trials to prevent type 1 diabetes.

Portsmouth visual field database: an audit of glaucoma progression.

To explore visual field (VF) progression in a cohort of secondary care-treated glaucoma and ocular hypertensive (OHT) patients. We extracted VFs from our database drawn from our normal clinical practice. VF series from 4177 eyes from 2208 patients who had five or more VFs were obtained, the 'better' eye was selected and the rate of VF progression was calculated using mean deviation (MD) data. The median rate of progression for the whole sample was -0.1 dB/year (interquartile range (IQR) -4 to 0 dB/year) over a median of 6.7 years (IQR 4.9-8.7). Of 2208 patients, 477 (21.2%) progressed at > -0.5 dB/year; 46 (2.1%) progressed at >-2.0 dB/year. Of those with a 'final MD' of worse than -10 dB (N=244) in their better eye; 14.0% were 'fast progressors' (>-2 dB/year), 33.7% 'moderate progressors' (-1 to -2 dB/year), and 28.8% 'slow progressors' (-0.3 dB to -1 dB/year). Of those with 'initial MD' better than -3 dB and those with worse than -3 dB, 31/1679 (1.8%) and 213/529 (40.3%) respectively, had a final MD of worse than -10 dB. Fast progressors, while important, are relatively rare. Moderate and slow progressors make up the majority of the progressing population within this data set. The risk of significant visual loss is much higher in those with initial damage. With increasing life expectancy, moderate and slow progressors may become increasingly clinically important.

ACSM4 Polymorphisms Are Associated With Rapid AIDS Progression in HIV-Infected Patients

: Our aim was to explore the association among ACSM4 and PECI polymorphisms and AIDS progression in 454 HIV-infected patients never treated with antiretroviral drugs (146 long-term nonprogressors, 228 moderate progressors, and 80 rapid progressors). For ACSM4 polymorphisms, rs7137120 AA/AG and rs7961991 CC/CT genotypes had higher odds of having a rapid AIDS progression [odds ratio (OR) = 3.21; 95% of confidence interval (95% CI) = 1.26 to 8.16; P = 0.014 and OR = 3.60; 95% CI = 1.38 to 9.36; P = 0.009, respectively]. Additionally, the ACSM4 haplotype integrated for both rs7961991 A and rs7137120 C alleles had higher odds of having a rapid AIDS progression (OR = 2.85; 95% CI = 1.28 to 6.25; P = 0.010). For PECI polymorphisms, no significant associations were found. In conclusion, ACSM4 polymorphisms might play a significant role in AIDS progression.

Retinal Blood Vessel Positional Shifts and Glaucoma Progression

To determine the characteristics and significance of retinal blood vessel (RBV) positional shifts over time in a cohort of patients with progressive glaucoma. Retrospective cohort study. Baseline and serial stereophotographs from 1 eye of 125 patients with open-angle glaucoma with ≥8 reliable Swedish interactive threshold algorithm standard visual fields (VFs) were included. On the basis of global rates of threshold sensitivity change, patients with glaucoma were divided into groups of minimal (<-0.02 decibels [dB]/year), moderate (-0.02 to-0.65 dB/year), or fast (≥-0.65 dB/year) progression. To determine whether graders' assessments of RBV positional shifts were false-positives, a control group consisting of 33 patients with glaucoma with 2 sets of photographs taken on the same day was included. Masked graders reviewed serial photographs aligned with automated alternation flicker (EyeIC, Narbeth, PA) and assessed them for the presence of any discrete RBV positional shifts (2 graders) and for traditional measures of structural progression (2 graders), including neuroretinal rim loss, parapapillary atrophy progression, and disc hemorrhage (DH). Presence or absence of RBV positional shifts, rates of VF progression, and presence or absence of traditional measures of structural progression. A total of 158 image sets (125 longitudinal and 33 same-day controls) from patients with glaucoma were included. Retinal blood vessel shifts were noted in 33 of 125 (26.4%) longitudinally followed glaucomatous eyes and 2 of 33 (6%) same-day control patients (P= 0.01). Agreement between graders I and II was 90.4% (kappa=0.77; P< 0.001). Eyes with RBV positional change progressed more rapidly than those without (-0.55 vs.-0.29 dB/year; 95% confidence interval [CI], 0.03-0.48); P= 0.03). Retinal blood vessel shift was present in 12.1% of minimal progressors versus 31.5% of moderate and fast progressors (P= 0.04). Rate of VF progression was statistically associated with RBV shift (odds ratio [OR], 2.2; 95% CI, 1.1-4.5; P= 0.03). Other variables significantly associated with RBV shift included neuroretinal rim loss (OR, 21.9; 95% CI, 5.7-83.6; P< 0.001) and DH (OR, 4.6; 95% CI, 1.5-15.5; P< 0.01). A multivariable model revealed that rim loss and DH, but not rate of functional change, were significantly associated with RBV shift. Retinal blood vessel positional shifts occurred in eyes with functionally progressive glaucoma, neuroretinal rim loss, and DH. This is a novel clinical finding that could help identify glaucoma progression or individuals at higher risk for future progression.

Improved Prediction of Rates of Visual Field Loss in Glaucoma Using Empirical Bayes Estimates of Slopes of Change

To describe and test a new methodology for estimation of rates of progressive visual field loss in glaucoma. This observational cohort study enrolled 643 eyes of 368 patients recruited from the Diagnostic Innovations in Glaucoma Study, followed for an average of 6.5±2.0 years. The visual field index was used to evaluate degree of visual field loss in standard automated perimetry. Growth mixture models were used to evaluate visual field index changes over time. Empirical Bayes estimates of best linear unbiased predictions (BLUPs) were used to obtain slopes of change based on the first 5 visual fields for each eye. These slopes were then used to predict future observations. The same procedure was done for ordinary least squares (OLS) estimates. The mean square error of the predictions was used to compare the predictive performance of the different methods. The growth mixture model successfully identified subpopulations of nonprogressors, slow, moderate, and fast progressors. The mean square error was significantly higher for OLS compared with the BLUP method (32.3 vs 13.9, respectively; P<0.001), indicating a better performance of the BLUP method to predict future observations. The benefit of BLUP predictions was especially evident in eyes with moderate and fast rates of change. Empirical Bayes estimates of rates of change performed significantly better than the commonly used technique of OLS regression in predicting future observations. Use of BLUP estimates should be considered when evaluating rates of functional change in glaucoma and predicting future impairment from the disease.

Identifying common trajectories of joint space narrowing over two years in knee osteoarthritis

Little is known about the natural history of knee osteoarthritis (OA). We sought to identify common patterns of joint space narrowing (JSN) in well-characterized knee OA patients in the placebo arm of a 2-year international study. We performed secondary data analyses of 622 adults ages 39-80 years in North America (n = 310) and Europe (n = 312) with symptomatic knee OA. Fluoroscopically positioned semiflexed anteroposterior radiographs were obtained at 0, 12, and 24 months. Group-based trajectory modeling was used to identify distinctive groups of individuals with similar trajectories of JSN, taking into account sex, age, and body mass index. Seven groups were identified. Four exhibited joint space width (JSW) stability over 2 years representing the most common trajectory (71%), which was unrelated to initial JSW. Atypical courses included slow, rapid, and moderate progressors; most had significant JSN at study entry. Slow progressors (20%) had a mean JSN of 0.2 mm over 2 years. Only 2% of the sample demonstrated rapid JSN (2.1 mm), while 7% had JSN of 0.7 mm. Rapid progressors tended to be men, while slow and moderate progressors were older and heavier. Most (70%) people with OA demonstrated no significant JSN over 2 years; 20% showed slow progression, 7% had moderate, and 2% had rapid JSN. Progressors tended to have less JSW at study entry and were older and heavier; rapid progressors were more likely to be men. Understanding common patterns of the course of knee OA may offer new opportunities to target those at greatest risk of disability.