Survival Analysis in the Presence of Competing Risks: The Example of Waitlisted Kidney Transplant Candidates

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long‐term mortality. In a typical analysis of time‐to‐event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of “independent censoring,” which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause‐specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation.     

High gestational weight gain and the risk of preterm birth and low birth weight: a systematic review and meta-analysis

ObjectiveMany women have high gestational weight gain (GWG), but potential neonatal consequences are not yet well quantified. We sought to determine the relationship between high GWG and preterm birth (PTB) and low birth weight (LBW) in singleton births.Data SourcesWe searched Medline and Embase and reference lists.Study SelectionTwo assessors independently performed all steps. We selected studies assessing high total or weekly GWG on PTB (< 37 weeks) and LBW (< 2500 grams).Data extraction and synthesisThirty-eight studies, 24 cohort and 14 case-control, were included involving 2 124 907 women. Most contained unadjusted data. Women with high total GWG had a decreased risk overall of PTB < 37 weeks (relative risk [RR] 0.75; 95% CI 0.60 to 0.96), PTB 32 to 36 weeks (RR 0.70; 95% CI 0.70 to 0.71), and < 32 weeks (RR 0.87; 95% CI 0.85 to 0.90). High GWG was associated with lower risk of LBW (RR 0.64; 95% CI 0.53 to 0.78). Women with the highest GWG had lower risks of LBW (RR 0.55; 95% CI 0.32 to 0.94) than women with moderately high GWG (RR 0.73; 95% CI 0.60 to 0.89). Women with the highest weekly GWG had greater risks of PTB (RR 1.51; 95% CI 1.47 to 1.55) than women with moderately high weekly GWG (RR 1.09; 95% CI 1.05 to 1.13). Women with high weekly GWG were at increased risk of PTB 32 to 36 weeks (RR 1.14; 95% CI 1.10 to 1.17 and < 32 weeks (RR 1.81; 95% CI 1.73 to 1.90).ConclusionAlthough women with high total GWG have lower unadjusted risks of PTB and LBW, high weekly GWG is associated with increased PTB, and more adjusted studies are needed, as are more studies in obese women. Potential benefits of high GWG for the infant must be balanced against maternal risks and other known infant risks such as high birth weight.     

Influence of length of time to diagnosis and treatment on the survival of children with acute lymphoblastic leukemia: A population-based study

The objectives were to describe times to diagnosis and initiation of treatment in pediatric ALL in Ontario from 1997 to 2007, and to measure their impact on OS and EFS. In 1000 children, the median times to diagnosis and treatment were both 1day (IQR = 1–2). Those who began treatment >3 days after diagnosis had inferior OS (AHR = 2.49; 95% CI = 1.40–4.43; p = 0.002), and inferior EFS (AHR = 1.73; 95% CI = 1.01–2.96; p = 0.047) compared to those who began treatment ≤3 days after diagnosis. There was no statistically significant relationship between time to diagnosis and survival. Longer time to treatment was associated with worse survival in pediatric ALL; reasons for this relationship may be multi-factorial.     

Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: A systematic review and meta-analysis

The role of leukapheresis and low-dose chemotherapy is unclear in decreasing early mortality in acute myeloid leukemia (AML) patients with hyperleukocytosis. This systematic review was conducted to describe early mortality (deaths during first induction) in patients with AML with an initial white blood count ≥ 100 × 10⁹ L⁻¹ stratified by the approach to leukapheresis and hydroxyurea/low-dose chemotherapy. Twenty-one studies were included. Weighted mean early deaths rate (20 studies, 1354 patients) was 20.1% (95% confidence interval 15.0–25.1). Neither leukapheresis strategy (p = 0.67) nor hydroxyurea/low-dose chemotherapy (p = 0.23) influenced the early death rate. Early mortality related to hyperleukocytosis in AML is not influenced by universal or selected use of leukapheresis or hydroxyurea/low-dose chemotherapy.     

Outpatient and oral antibiotic management of low-risk febrile neutropenia are effective in children—a systematic review of prospective trials

Background  

There is no consensus on whether therapeutic intensity can be reduced safely in children with low-risk febrile neutropenia (FN). Our primary objective was to determine whether there is a difference in efficacy between outpatient and inpatient management of children with low-risk FN. Our secondary objective was to compare oral and parenteral antibiotic therapy in this population.     

Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials

OBJECTIVE

The effect of fructose on cardiometabolic risk in humans is controversial. We conducted a systematic review and meta-analysis of controlled feeding trials to clarify the effect of fructose on glycemic control in individuals with diabetes.

RESEARCH DESIGN AND METHODS

We searched MEDLINE, EMBASE, and the Cochrane Library (through 22 March 2012) for relevant trials lasting ≥7 days. Data were aggregated by the generic inverse variance method (random-effects models) and expressed as mean difference (MD) for fasting glucose and insulin and standardized MD (SMD) with 95% CI for glycated hemoglobin (HbA_1c) and glycated albumin. Heterogeneity was assessed by the Cochran Q statistic and quantified by the I² statistic. Trial quality was assessed by the Heyland methodological quality score (MQS).

RESULTS

Eighteen trials (n = 209) met the eligibility criteria. Isocaloric exchange of fructose for carbohydrate reduced glycated blood proteins (SMD −0.25 [95% CI −0.46 to −0.04]; P = 0.02) with significant intertrial heterogeneity (I² = 63%; P = 0.001). This reduction is equivalent to a ∼0.53% reduction in HbA_1c. Fructose consumption did not significantly affect fasting glucose or insulin. A priori subgroup analyses showed no evidence of effect modification on any end point.

CONCLUSIONS

Isocaloric exchange of fructose for other carbohydrate improves long-term glycemic control, as assessed by glycated blood proteins, without affecting insulin in people with diabetes. Generalizability may be limited because most of the trials were <12 weeks and had relatively low MQS (<8). To confirm these findings, larger and longer fructose feeding trials assessing both possible glycemic benefit and adverse metabolic effects are required.The number of people with type 2 diabetes is likely to double during the next 20 years (1), leading to an increased burden of cardiovascular disease (2), renal failure (2), blindness (2), and risk of colon, breast, and other cancers (3). Diabetes profoundly alters macronutrient metabolism; the roles of diet and especially carbohydrate type and quality are therefore of considerable interest. Since 1970, the total availability of sugars has increased by ∼20% (4), and high-fructose corn syrup now represents nearly 50% of caloric sweetener use in the United States (4,5). Increased total fructose consumption (from both sucrose and high-fructose corn syrup) has been implicated in the development of the obesity epidemic in the United States (6) and has been singled out in diabetes guidelines because of concerns about its effects on lipids.Diabetes associations (2,7,8) have taken a harm-reduction approach to fructose recommendations, setting an upper threshold for intake that is based on putative adverse effects on serum lipids. The American Diabetes Association guidelines, however, acknowledge that fructose produces a lower glycemic response in people with diabetes when it replaces sucrose and starch in the diet (7). Fructose has also been shown to improve glycemia without adversely affecting lipids when exchanged for other carbohydrate in controlled feeding trials in people with type 2 diabetes (9–15). In the absence of clear guidance on the role of fructose in glycemic control, we conducted a systematic review and meta-analysis of controlled feeding trials to assess the effects of isocaloric, oral fructose exchange for carbohydrates on fasting glucose, fasting insulin, and glycated blood proteins (glycated hemoglobin [HbA_1c], glycated albumin, and fructosamine) in individuals with diabetes.