Effect of a FIT-Based Colorectal Cancer Screening Program on Mortality Estimated by the Regression Discontinuity Design.

The fecal immunochemical test (FIT) has been implemented in colorectal cancer (CRC) screening programs, but effect evaluations are lacking. We evaluated the effect of a positive FIT on all-cause and CRC mortality using the regression discontinuity design. The Danish CRC screening program invites all residents 50-74 years old, using a 20-µg hemoglobin/g feces cutoff for colonoscopy referral. In this cohort study, we followed all first-time screening participants from 2014-2019 until 2020. We estimated the local effect of screening results, of just above the cutoff vs. just below, as hazard ratios (HRs) between models fitted at each side of the cutoff. We conducted the analysis within a narrow hemoglobin range (≥17 and <23, n = 16,428) and a wider range (≥14 and <26, n = 35,353). Those screened just above the cutoff had lower all-cause mortality compared with below (HR = 0.87, 95% confidence interval: 0.69; 1.10), estimated from the narrow range. The CRC mortality analysis had few outcomes. In the wider range, those with a FIT just above the cutoff had a lower hazard of CRC mortality compared with just below the cutoff (HR = 0.49, 95% confidence interval: 0.17; 1.41). A FIT result just above the cutoff, leading to referral to colonoscopy, pointed towards reduced all-cause and CRC mortality compared with just below the cutoff.

Elevated potassium levels in patients with chronic kidney disease: occurrence, risk factors and clinical outcomes-a Danish population-based cohort study.

Background: Data on the true burden of hyperkalemia (HK) in patients with chronic kidney disease (CKD) in a real-world setting are scarce. Methods: The incidence rate of HK [first blood test with an elevated blood potassium level level >5.0 mmol/L] in primary or hospital care was assessed in a population-based cohort of all newly diagnosed CKD patients [second estimated glomerular filtration rate (eGFR) measurement <60 mL/min/1.73 m2 or hospital diagnosis] in northern Denmark. Risk factors and clinical outcomes were compared for CKD patients with HK and matched CKD patients without HK. Results: Of 157 766 patients with CKD, 28% experienced HK, for an overall HK incidence rate of 70/1000 person-years. Among patients with Stage 3A, 3B, 4 or 5 CKD, 9, 18, 31 and 42%, respectively, experienced HK within the first year. Important HK risk factors included diabetes {prevalence ratio [PR] 1.74 [95% confidence interval (CI) 1.69-1.79]}, heart failure [PR 2.31 (95% CI 2.23-2.40)] and use of angiotensin-converting enzyme inhibitors [PR 1.45 (95% CI 1.42-1.48)], potassium supplements [PR 1.59 (95% CI 1.55-1.62)] or spironolactone [PR 2.53 (95% CI 2.44-2.63)]. In CKD patients who developed HK, 34% had any acute hospitalization 6 months before the HK event, increasing to 57% 6 months after HK [before-after risk ratio 1.72 (95% CI 1.69-1.74)]. The 6-month mortality following HK was 26%, versus 6% in matched non-HK patients. Compared with non-HK patients, 6-month hazard ratios for any acute hospitalization in HK patients were 2.11-fold higher, including hazard ratios of 2.07 for cardiac diagnoses, 2.29 for ventricular arrhythmias, 3.26 for cardiac arrest, 4.77 for intensive care and 4.85 for death. Conclusions: More than one in four CKD patients develops HK. Patients with severe CKD, diabetes, heart failure or use of spironolactone are at high risk. HK is associated with severe clinical outcomes.

Development of a 5-year risk prediction model for type 2 diabetes in individuals with incident HbA1c-defined pre-diabetes in Denmark.

INTRODUCTION: Pre-diabetes increases the risk of type 2 diabetes, but data are sparse on predictors in a population-based clinical setting. We aimed to develop and validate prediction models for 5-year risks of progressing to type 2 diabetes among individuals with incident HbA1c-defined pre-diabetes. RESEARCH DESIGN AND METHODS: In this population-based cohort study, we used data from the Danish National Health Survey (DNHS; n=486 495), linked to healthcare registries and nationwide laboratory data in 2012-2018. We included individuals with a first HbA1c value of 42-47 mmol/mol (6.0%-6.4%), without prior indications of diabetes. To estimate individual 5-year cumulative incidences of type 2 diabetes (HbA1c ≥48 mmol/mol (6.5%)), Fine-Gray survival models were fitted in random 80% development samples and validated in 20% validation samples. Potential predictors were HbA1c, demographics, prescriptions, comorbidities, socioeconomic factors, and self-rated lifestyle. RESULTS: Among 335 297 (68.9%) participants in DNHS with HbA1c measurements, 26 007 had pre-diabetes and were included in the study. Median HbA1c was 43.0 mmol/mol (IQR 42.0-44.0 mmol/mol, 6.1% (IQR 6.0%-6.2%)), median age was 69.6 years (IQR 61.0-77.1 years), and 51.9% were women. During a median follow-up of 2.7 years, 11.8% progressed to type 2 diabetes and 10.1% died. The final prediction model included HbA1c, age, sex, body mass index (BMI), any antihypertensive drug use, pancreatic disease, cancer, self-reported diet, doctor's advice to lose weight or change dietary habits, having someone to talk to, and self-rated health. In the validation sample, the 5-year area under the curve was 72.7 (95% CI 71.2 to 74.3), and the model was well calibrated. CONCLUSIONS: In addition to well-known pre-diabetes predictors such as age, sex, and BMI, we found that measures of self-rated lifestyle, health, and social support are important and modifiable predictors for diabetes. Our model had an acceptable discriminative ability and was well calibrated.

Type 2 diabetes classification: a data-driven cluster study of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort.

INTRODUCTION: A Swedish data-driven cluster study identified four distinct type 2 diabetes (T2D) clusters, based on age at diagnosis, body mass index (BMI), hemoglobin A1c (HbA1c) level, and homeostatic model assessment 2 (HOMA2) estimates of insulin resistance and beta-cell function. A Danish study proposed three T2D phenotypes (insulinopenic, hyperinsulinemic, and classical) based on HOMA2 measures only. We examined these two new T2D classifications using the Danish Centre for Strategic Research in Type 2 Diabetes cohort. RESEARCH DESIGN AND METHODS: In 3529 individuals, we first performed a k-means cluster analysis with a forced k-value of four to replicate the Swedish clusters: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild age-related (MARD), and mild obesity-related (MOD) diabetes. Next, we did an analysis open to alternative k-values (ie, data determined the optimal number of clusters). Finally, we compared the data-driven clusters with the three Danish phenotypes. RESULTS: Compared with the Swedish findings, the replicated Danish SIDD cluster included patients with lower mean HbA1c (86 mmol/mol vs 101 mmol/mol), and the Danish MOD cluster patients were less obese (mean BMI 32 kg/m2 vs 36 kg/m2). Our data-driven alternative k-value analysis suggested the optimal number of T2D clusters in our data to be three, rather than four. When comparing the four replicated Swedish clusters with the three proposed Danish phenotypes, 81%, 79%, and 69% of the SIDD, MOD, and MARD patients, respectively, fitted the classical T2D phenotype, whereas 70% of SIRD patients fitted the hyperinsulinemic phenotype. Among the three alternative data-driven clusters, 60% of patients in the most insulin-resistant cluster constituted 76% of patients with a hyperinsulinemic phenotype. CONCLUSION: Different HOMA2-based approaches did not classify patients with T2D in a consistent manner. The T2D classes characterized by high insulin resistance/hyperinsulinemia appeared most distinct.

Diabetic Polyneuropathy Early in Type 2 Diabetes Is Associated With Higher Incidence Rate of Cardiovascular Disease: Results From Two Danish Cohort Studies.

OBJECTIVE: Symptoms indicative of diabetic polyneuropathy (DPN) early in type 2 diabetes may act as a marker for cardiovascular disease (CVD) and death. RESEARCH DESIGN AND METHODS: We linked data from two Danish type 2 diabetes cohorts, the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) and the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), to national health care registers. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was completed at diabetes diagnosis in ADDITION-Denmark and at a median of 4.6 years after diagnosis of diabetes in DD2. An MNSIq score ≥4 was considered as indicative of DPN. Using Poisson regressions, we computed incidence rate ratios (IRRs) of CVD and all-cause mortality comparing MNSIq scores ≥4 with scores <4. Analyses were adjusted for a range of established CVD risk factors. RESULTS: In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores <4, MNSIq scores ≥4 were associated with higher incidence rate of CVD, with IRRs of 1.79 (95% CI 1.38-2.31) in ADDITION-Denmark, 1.57 (CI 1.27-1.94) in the DD2, and a combined IRR of 1.65 (CI 1.41-1.95) in a fixed-effect meta-analysis. MNSIq scores ≥4 did not associate with mortality; combined mortality rate ratio was 1.11 (CI 0.83-1.48). CONCLUSIONS: The MNSIq may be a tool to identify a subgroup within individuals with newly diagnosed type 2 diabetes with a high incidence rate of subsequent CVD. MNSIq scores ≥4, indicating DPN, were associated with a markedly higher incidence rate of CVD, beyond that conferred by established CVD risk factors.

Lessons Learned Using Real-World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia.

Regulatory agencies are increasingly considering real-world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim vs. standard-of-care (SOC) therapy among patients with recently diagnosed (≤12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the end point of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary end point. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group vs. SOC, precision was limited because of small study size (median difference was 11 × 109 /L (95% CI: -59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit-for-purpose data sources with sufficient sample size, data elements, and follow-up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision makers and the data.