Maria Kohl

PSHREG: a SAS macro for proportional and nonproportional subdistribution hazards regression.

Highlights • The %pshreg SAS macro fits Fine-Gray models for competing risks.• The macro first modifies a given data set and then uses PROC PHREG for analysis.• Many useful features of PROC PHREG can now be applied to a Fine-Gray model.• Time-dependent effects can be accommodated by time-by-covariate interactions.• For small data sets, the Firth correction is available.

Modifiable lifestyle and social factors affect chronic kidney disease in high-risk individuals with type 2 diabetes mellitus

This observational study examined the association between modifiable lifestyle and social factors on the incidence and progression of early chronic kidney disease (CKD) among those with type 2 diabetes. All 6972 people from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) with diabetes but without macroalbuminuria were studied. CKD progression was defined as decline in GFR of more than 5% per year, progression to end-stage renal disease, microalbuminuria, or macroalbuminuria at 5.5 years. Lifestyle/social factors included tobacco and alcohol use, physical activity, stress, financial worries, the size of the social network and education. Adjustments were made for known risks such as age, diabetes duration, GFR, albuminuria, gender, body mass index, blood pressure, fasting plasma glucose, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers use. Competing risk of death was considered. At study end, 31% developed CKD and 15% had died. The social network score (SNS) was a significant independent risk factor of CKD and death, reducing the risk by 11 and 22% when comparing the third to the first tertile of the SNS (odds ratios of CKD 0.89 and death 0.78). Education showed a significant association with CKD but stress and financial worries did not. Those with moderate alcohol consumption had a significantly decreased CKD risk compared with nonusers. Regular physical activity significantly decreased the risk of CKD. Thus, lifestyle is a determinant of kidney health in people at high cardiovascular risk with diabetes.

Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens (TCA), but the clinical significance of this finding is uncertain. Fifty cHLs expressing any TCA on the HRS cells (TCA-cHL) were identified in two cohorts (National Cancer Institute, n = 38; Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor γ rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for TCA (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the TCA-cHL group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the TCA, CD4 and CD2 were most commonly expressed, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. During a median follow up of 113 months, TCA expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84]; P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001). TCA-cHL often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with TCA-negative cHLs.

Validating the impact of a molecular subtype in ovarian cancer on outcomes: A study of the OVCAD Consortium

Most patients with epithelial ovarian cancer (EOC) are diagnosed at advanced stage and have a poor prognosis. However, a small proportion of these patients will survive, whereas others will die very quickly. Clinicopathological factors do not allow precise identification of these subgroups. Thus, we have validated a molecular subclassification as new prognostic factor in EOC. One hundred and ninety‐four patients with Stage II–IV EOC were characterized by whole‐genome expression profiling of tumor tissues and were classified using a published 112 gene set, derived from an International Federation of Gynecology and Obstetrics (FIGO) stage‐directed supervised classification approach. The 194 tumor samples were classified into two subclasses comprising 95 (Subclass 1) and 99 (Subclass 2) tumors. All nine FIGO II tumors were grouped in Subclass 1 (P = 0.001). Subclass 2 (54% of advanced‐stage tumors) was significantly correlated with peritoneal carcinomatosis and non‐optimal debulking. Patients with Subclass 2 tumors had a worse overall survival for both serous and non‐serous histological subtypes, as revealed by univariate analysis (hazard ratios [HR] of 3.17 and 17.11, respectively; P ≤ 0.001) and in models corrected for relevant clinicopathologic parameters (HR 2.87 and 12.42, respectively; P ≤ 0.023). Significance analysis of microarrays revealed 2082 genes that were differentially expressed in advanced‐grade serous tumors of both subclasses and the focal adhesion pathway as the most deregulated pathway. In the present validation study, we have shown that, in advanced‐stage serous ovarian cancer, two approximately equally large molecular subtypes exist, independent of classical clinocopathological parameters and presenting with highly different whole‐genome expression profiles and a markedly different overall survival. Similar results were obtained in a small cohort of patients with non‐serous tumors. (Cancer Sci 2012; 103: 1334–1341)

Relevance of gamma-glutamyltransferase – a marker for apoptotic balance – in predicting tumor stage and prognosis in cervical cancer

INTRODUCTION Recent large epidemiologic population-based studies identified gamma-glutamyltransferase (GGT) as a marker for increased cervical cancer incidence. Furthermore, high levels of GGT seem to increase the risk of progression of high-grade cervical dysplasia to invasive carcinoma. Therefore, we evaluated the association between pre-therapeutic serum GGT levels, tumor stage and prognosis in patients with cervical cancer. MATERIALS AND METHODS In this multi-center trial, pre-therapeutic GGT levels were examined in 692 patients with cervical cancer. GGT levels were correlated with clinico-pathological parameters. Patients were assigned to previously described GGT risk groups and uni- and multivariable survival analyses were performed. RESULTS GGT serum levels were associated with FIGO stage (p<0.0001) and age (r=0.2, p<0.0001) but not with lymph node involvement (p=0.85), and histological type (p=0.98). High-risk GGT group affiliation (p=0.01 and p<0.0001) was associated with poor disease-free and overall survival in a univariate analysis, but not in a multivariable Cox-regression model (p=0.59 and p=0.171). We further investigated the association between prognosis and GGT and observed a linear correlation between GGT and prognosis. Therefore we were not able to identify a clear prognostic cut-off value for GGT in patients with cervical cancer. CONCLUSIONS High GGT--a marker for apoptosis and cervical cancer risk--is associated with advanced tumor stage in patients with cervical cancer.

A combined blood based gene expression and plasma protein abundance signature for diagnosis of epithelial ovarian cancer - a study of the OVCAD consortium

BackgroundThe immune system is a key player in fighting cancer. Thus, we sought to identify a molecular ‘immune response signature’ indicating the presence of epithelial ovarian cancer (EOC) and to combine this with a serum protein biomarker panel to increase the specificity and sensitivity for earlier detection of EOC.MethodsComparing the expression of 32,000 genes in a leukocytes fraction from 44 EOC patients and 19 controls, three uncorrelated shrunken centroid models were selected, comprised of 7, 14, and 6 genes. A second selection step using RT-qPCR data and significance analysis of microarrays yielded 13 genes (AP2A1, B4GALT1, C1orf63, CCR2, CFP, DIS3, NEAT1, NOXA1, OSM, PAPOLG, PRIC285, ZNF419, and BC037918) which were finally used in 343 samples (90 healthy, six cystadenoma, eight low malignant potential tumor, 19 FIGO I/II, and 220 FIGO III/IV EOC patients). Using new 65 controls and 224 EOC patients (thereof 14 FIGO I/II) the abundances of six plasma proteins (MIF, prolactin, CA125, leptin, osteopondin, and IGF2) was determined and used in combination with the expression values from the 13 genes for diagnosis of EOC.ResultsCombined diagnostic models using either each five gene expression and plasma protein abundance values or 13 gene expression and six plasma protein abundance values can discriminate controls from patients with EOC with Receiver Operator Characteristics Area Under the Curve values of 0.998 and bootstrap .632+ validated classification errors of 3.1% and 2.8%, respectively. The sensitivities were 97.8% and 95.6%, respectively, at a set specificity of 99.6%.ConclusionsThe combination of gene expression and plasma protein based blood derived biomarkers in one diagnostic model increases the sensitivity and the specificity significantly. Such a diagnostic test may allow earlier diagnosis of epithelial ovarian cancer.

Plasma proteomics classifiers improve risk prediction for renal disease in patients with hypertension or type 2 diabetes

Objective: Micro and macroalbuminuria are strong risk factors for progression of nephropathy in patients with hypertension or type 2 diabetes. Early detection of progression to micro and macroalbuminuria may facilitate prevention and treatment of renal diseases. We aimed to develop plasma proteomics classifiers to predict the development of micro or macroalbuminuria in hypertension or type 2 diabetes. Methods: Patients with hypertension (n = 125) and type 2 diabetes (n = 82) were selected for this case-control study from the Prevention of REnal and Vascular ENd-stage Disease cohort and the Steno Diabetes Center. Cases transitioned from normo to microalbuminuria, or from micro to macroalbuminuria. Controls, matched for age, sex, and baseline albuminuria stage, did not transition. Follow-up was 3.0 ± 0.9 years. Plasma proteomics profiles were measured by liquid chromatography-electrospray-trap mass-spectrometry. Classifiers were developed and cross-validated for prediction of transition in albuminuria stage. Improvement in risk prediction was tested on top of a reference model of baseline albuminuria, estimated glomerular filtration rate, and renin–angiotensin–aldosterone system intervention. Results: In hypertensive patients, the classifier improved risk prediction for transition in albuminuria stage on top of the reference model (C-index from 0.69 to 0.78; P < 0.01). In type 2 diabetes, the classifier improved risk prediction for transition from micro to macroalbuminuria (C-index from 0.73 to 0.80; P = 0.04). In both diseases, the identified peptides were linked to pathways recognized to contribute to nephropathy, including fibrosis, inflammation, angiogenesis, and mineral metabolism. Conclusions: Plasma proteomics predict the transition in albuminuria stage beyond established renal risk markers in hypertension or type 2 diabetes. External validation is needed to assess reproducibility.

Urine Osmolarity and Risk of Dialysis Initiation in a Chronic Kidney Disease Cohort – a Possible Titration Target?

Background Increasing evidence is linking fluid intake, vasopressin suppression and osmotic control with chronic kidney disease progression. Interestingly, the association between urine volume, urine osmolarity and risk of dialysis initiation has not been studied in chronic kidney disease patients before. Objective To study the relationship between urine volume, urine osmolarity and the risk of initiating dialysis in chronic kidney disease. Design In a retrospective cohort analysis of 273 patients with chronic kidney disease stage 1–4 we assessed the association between urine volume, urine osmolarity and the risk of dialysis by a multivariate proportional sub-distribution hazards model for competing risk data according to Fine and Gray. Co-variables were selected via the purposeful selection algorithm. Results Dialysis was reached in 105 patients over a median follow-up period of 92 months. After adjustment for age, baseline creatinine clearance, other risk factors and diuretics, a higher risk for initiation of dialysis was found in patients with higher urine osmolarity. The adjusted sub-distribution hazard ratio for initiation of dialysis was 2.04 (95% confidence interval, 1.06 to 3.92) for each doubling of urine osmolarity. After 72 months, the estimated adjusted cumulative incidence probabilities of dialysis were 15%, 24%, and 34% in patients with a baseline urine osmolarity of 315, 510, and 775 mosm/L, respectively. Conclusions We conclude that higher urine osmolarity is associated with a higher risk of initiating dialysis. As urine osmolarity is a potentially modifiable risk factor, it thus deserves further, prospective research as a potential target in chronic kidney disease progression.

Renal function in heart failure: a disparity between estimating function and predicting mortality risk

To compare the predictive value of estimated renal function calculated by the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD‐EPI), four‐variable Modification of Diet in Renal Disease (eGFRMDRD‐4), and Cockcroft–Gault [estimated creatinine clearance (eCcr)] equation in terms of all‐cause mortality in heart failure. Renal function is an important prognostic factor in heart failure. Established methods of estimating renal function are known to under‐/overestimate true function in certain settings.

Dietary risk factors for incidence or progression of chronic kidney disease in individuals with type 2 diabetes in the European Union

BACKGROUND Although the prevalence of chronic kidney disease (CKD) is ∼ 30% in the group of people with diabetes, data on interventions in the very early stage of the disease are still missing. Furthermore, the effects of modifiable lifestyle factors such as nutrition on incidence and progression of CKD in patients with diabetes in Europe remain elusive. METHODS We analyzed whether diet quality and adherence to dietary guidelines using the modified Alternate Healthy Eating Index (mAHEI) score was associated with CKD incidence or progression after 5.5 years in 3088 European participants of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) with type 2 diabetes and baseline normo- or micro-albuminuria. Death was considered as a competing risk in the multinomial logit regression models, which were adjusted for age, gender, duration of diabetes, ONTARGET randomization, baseline albuminuria and glomerular filtration rate (GFR). We also estimated the potential impact on population health of improvement in diet quality. RESULTS At study end, 450 (14.6%) participants had died and 926 (30%) had experienced the renal endpoint of incidence or progression of CKD, of which 422 (13.7%) participants had progressed to micro- or macro-albuminuria, 596 (19.3%) had a GFR-decline of >5% per year and 18 (0.6%) had developed end-stage renal disease. Participants in the healthiest tertile of the mAHEI score had a decreased risk of incidence or progression of CKD (odds ratio 0.8, 95% confidence interval 0.68-0.94) and death (0.65, 0.52-0.81) compared with participants in the least healthy tertile. If individuals with a suboptimal dietary quality (e.g. mAHEI < 28) were able to improve their diet to an mAHEI of 28, 3.2% of CKD incidence or progression and 10.0% of deaths might be avoided in 5.5 years. CONCLUSIONS If the association between diet and these endpoints is causal, then optimizing diet quality in individuals with diabetes who have no CKD or very early CKD would have substantial population benefits in terms of prevention of CKD incidence or progression and mortality in this high-risk population.