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In clinical research, we are often interested in assessing how a biomarker changes with time, and whether it could be used as a surrogate marker when evaluating the efficacy of a new drug. However, when the longitudinal marker is correlated with survival, linear mixed models for longitudinal data may be inappropriate. By contrast, it may be possible to recover information from the so-called informative censoring by modelling both the longitudinal information and the survival process. The objective of this work is to jointly model longitudinal and survival data to assess surrogacy. Two competitive modelling strategies were used, either a multistate model summarizing the course of longitudinal data and occurrence of disease progression or death, or a joint longitudinal-survival model. We present both analyses based on a case study from two randomized clinical trials that enrolled patients with stage A chronic lymphocytic leukaemia (CLL) in order to obtain further insights into these different approaches.

An estimated 60% of kidney transplant recipients have mineral bone disease and about 0.5% break their hip within the first year after transplantation. We conducted a systematic review of benefits and harms of bisphosphonates in kidney transplant recipients. We searched CENTRAL (Issue 5, 2015) for randomized controlled trials in all languages and screened the reference list of an earlier Cochrane review. One reviewer identified the trials, extracted all data, and assessed risk of bias. Meta-analysis used a random effects model, with results expressed as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). Bisphosphonates have uncertain effects on death (RR 0.45, CI 0.04-4.69) and vertebral fractures (RR 0.58, CI 0.24-1.43, I(2) 0%). Bisphosphonates moderately to importantly reduce the loss of vertebral bone mineral density (MD 5.98%, CI 3.77-8.18% change from baseline in g calcium/cm² at 12 months, I(2) 91%) and femoral bone mineral density (MD 5.57%, 3.12-8.01% change from baseline in g calcium/cm² at 12 months, I(2) 69%). At this stage, insufficient evidence exists to support routine use of bisphosphonates to reduce fracture risk after kidney transplantation. Data on important health outcomes are lacking, surrogate outcomes poorly reflect bone quality in kidney transplant recipients, and serious adverse events are not studied and reported systematically.

A 36-year-old man with no significant past medical history presented with two-month abdominal distention, night sweats, and weight loss of 15 Ib. He had no known exposure to tuberculosis. PPD test was negative prior to the hospital admission. Physical examination was notable for new onset ascites, but no superficial lymphadenopathy or stigmata of chronic liver disease was found. CT scan demonstrated enlarged mesenteric lymph nodes, and prominent retroperitoneal lymph nodes along with moderate ascites and omental infiltration. Diagnostic paracentesis yielded WBC of 295/mm3, lymphocytic predominance (70%), and serum ascitic albumin gradient of 0.1, consistent with exudate. Both the ascitic culture and AFB smear were negative, and ascitic cytology revealed nonmalignant cells. Exploratory laparoscopy for excisional biopsy of mesenteric lymph nodes was performed. Pathologic findings revealed caseous granulomas with scattered multinucleated giant cells. Mesenteric lymph node tissue culture subsequently grewMycobacterium tuberculosiscomplex and the diagnosis of peritoneal tuberculosis was confirmed. The patient was started on quadruple therapy. A couple of days after the antibiotics were started, the small bowel obstruction started to resolve with resumption of bowel movements and tolerance of oral intake. A week later, ascites stopped accumulating and fever was no longer noted. He has been well and continues to be under observation.

BACKGROUND: Gait acquisition is supported by changes in the neuromusculoskeletal system of the child. Changes in the dimensions of the body structures resulting from the growth of the child partly explain gait improvement in the first year of life. OBJECTIVES: To evaluate whether changes in body mass and leg length modulate the effect of independent gait practice (experience) on gait speed and stride length. METHOD: Thirty-two infants with normal development were monitored monthly from the acquisition of independent gait until six months post-acquisition. Longitudinal evaluations included measurements of the body mass and leg length of each child. Temporospatial variables of gait (speed and stride length) were documented using the Qualisys Pro-reflex(r) system. The data were analyzed using multilevel regression models, with a significance level of α=0.05. RESULTS: An effect of the practice time on speed (p CONTEXTUALIZAÇÃO: A aquisição da marcha é suportada por mudanças no sistema neuromusculoesquelético da criança. a literatura aponta que modificações nas dimensões das estruturas corporais resultantes do crescimento da criança explicam, em parte, o aprimoramento da marcha no primeiro ano de vida. OBJETIVOS: Avaliar se mudanças na massa corporal e comprimento da perna modulam o efeito da prática da marcha independente nos seguintes parâmetros da marcha: velocidade e comprimento da passada. MÉTODO: Trinta e dois lactentes com desenvolvimento normal foram acompanhados mensalmente a partir da aquisição da marcha independente até seis meses pós-aquisição. Avaliações longitudinais incluíram mensurações da massa corporal e do comprimento da perna de cada criança. As variáveis temporoespaciais da marcha (velocidade e comprimento da passada) foram documentadas utilizando-se o sistema Qualisys Pro-Reflex (r) . Os dados foram analisados por modelos de regressão multinível, com nível de significância α=0,05. RESULTADOS: Encontrou-se um efeito do tempo de prática nas medidas de velocidade (p

A 36-year-old man with no significant past medical history presented with two-month abdominal distention, night sweats, and weight loss of 15 Ib. He had no known exposure to tuberculosis. PPD test was negative prior to the hospital admission. Physical examination was notable for new onset ascites, but no superficial lymphadenopathy or stigmata of chronic liver disease was found. CT scan demonstrated enlarged mesenteric lymph nodes, and prominent retroperitoneal lymph nodes along with moderate ascites and omental infiltration. Diagnostic paracentesis yielded WBC of 295/mm3, lymphocytic predominance (70%), and serum ascitic albumin gradient of 0.1, consistent with exudate. Both the ascitic culture and AFB smear were negative, and ascitic cytology revealed nonmalignant cells. Exploratory laparoscopy for excisional biopsy of mesenteric lymph nodes was performed. Pathologic findings revealed caseous granulomas with scattered multinucleated giant cells. Mesenteric lymph node tissue culture subsequently grew Mycobacterium tuberculosis complex and the diagnosis of peritoneal tuberculosis was confirmed. The patient was started on quadruple therapy. A couple of days after the antibiotics were started, the small bowel obstruction started to resolve with resumption of bowel movements and tolerance of oral intake. A week later, ascites stopped accumulating and fever was no longer noted. He has been well and continues to be under observation.

Background Joint modeling of longitudinal and survival data has been increasingly considered in clinical trials, notably in cancer and AIDS. In critically ill patients admitted to an intensive care unit (ICU), such models also appear to be of interest in the investigation of the effect of treatment on severity scores due to the likely association between the longitudinal score and the dropout process, either caused by deaths or live discharges from the ICU. However, in this competing risk setting, only cause-specific hazard sub-models for the multiple failure types data have been used. Methods We propose a joint model that consists of a linear mixed effects submodel for the longitudinal outcome, and a proportional subdistribution hazards submodel for the competing risks survival data, linked together by latent random effects. We use Markov chain Monte Carlo technique of Gibbs sampling to estimate the joint posterior distribution of the unknown parameters of the model. The proposed method is studied and compared to joint model with cause-specific hazards submodel in simulations and applied to a data set that consisted of repeated measurements of severity score and time of discharge and death for 1,401 ICU patients. Results Time by treatment interaction was observed on the evolution of the mean SOFA score when ignoring potentially informative dropouts due to ICU deaths and live discharges from the ICU. In contrast, this was no longer significant when modeling the cause-specific hazards of informative dropouts. Such a time by treatment interaction persisted together with an evidence of treatment effect on the hazard of death when modeling dropout processes through the use of the Fine and Gray model for sub-distribution hazards. Conclusions In the joint modeling of competing risks with longitudinal response, differences in the handling of competing risk outcomes appear to translate into the estimated difference in treatment effect on the longitudinal outcome. Such a modeling strategy should be carefully defined prior to analysis.