Moshe Hoshen

Tumor growth rates derived from data for patients in a clinical trial correlate strongly with patient survival: a novel strategy for evaluation of clinical trial data.

PURPOSE The slow progress in developing new cancer therapies can be attributed in part to the long time spent in clinical development. To hasten development, new paradigms especially applicable to patients with metastatic disease are needed. PATIENTS AND METHODS We present a new method to predict survival using tumor measurement data gathered while a patient with cancer is receiving therapy in a clinical trial. We developed a two-phase equation to estimate the concomitant rates of tumor regression (regression rate constant d) and tumor growth (growth rate constant g). RESULTS We evaluated the model against serial levels of prostate-specific antigen (PSA) in 112 patients undergoing treatment for prostate cancer. Survival was strongly correlated with the log of the growth rate constant, log(g) (Pearson r = -0.72) but not with the log of the regression rate constants, log(d) (r = -0.218). Values of log(g) exhibited a bimodal distribution. Patients with log(g) values above the median had a mortality hazard of 5.14 (95% confidence interval, 3.10-8.52) when compared with those with log(g) values below the median. Mathematically, the minimum PSA value (nadir) and the time to this minimum are determined by the kinetic parameters d and g, and can be viewed as surrogates. CONCLUSIONS This mathematical model has applications to many tumor types and may aid in evaluating patient outcomes. Modeling tumor progression using data gathered while patients are on study, may help evaluate the ability of therapies to prolong survival and assist in drug development.

Seasonality of Asthma: A Retrospective Population Study

OBJECTIVES: Seasonal variations in asthma are widely recognized, with the highest incidence during September. This retrospective population study aimed to investigate whether this holds true in a large group of asthmatic children in primary care and to assess the impact of age, gender, urban/rural living, and population sector. METHODS: The key study outcomes were the diagnosis of asthma exacerbations and asthma medication prescriptions, recorded by family physicians during 2005 to 2009. These were analyzed by “week of diagnosis” in Clalit Health Services’ electronic medical record database. Regression models were built to assess relative strength of secular trends, seasonality, and age-group in explaining the incidence of asthma exacerbations. RESULTS: A total of 919 873 children aged 2 to 15 years were identified. Of these, 82 234 (8.9%) were asthmatic, 61.6% boys and 38.4% girls; 49.1% aged 2 to 5 years, 24.1% 6 to 9 years, and 26.8% 10 to 15 years. We observed a 2.01-fold increase in pediatric asthma exacerbations and 2.28-fold increase in prescriptions of asthma bronchodilator medications during September (weeks 37–39 vs weeks 34–36) compared with August. The association between the opening of school and the incidence of asthma-related visits to the primary care physician was greatest in children aged 2 to 5 years (odds ratio, 2.15) and 6 to 11 years (1.90-fold). Adolescents (age 12–15 years) had a lesser peak (1.81-fold). In late fall there was a second rise, lasting with fluctuations throughout winter, with a trough in summer. CONCLUSIONS: Returning to school after summer is strongly associated with an increased risk for asthma exacerbations and unscheduled visits to the primary care physician.

Effectiveness of dasabuvir/ombitasvir/paritaprevir/ritonavir for hepatitis C virus in clinical practice: A population-based observational study

Background Direct acting antivirals for hepatitis C virus have shown dramatic results in clinical trials. However, their effectiveness has yet to be demonstrated within observational cohorts which lack exclusion criteria found in randomized control trials. Aim To determine the effectiveness of dasabuvir/ombitasvir/paritaprevir/ritonavir in achieving sustained virological response. Methods Retrospective observational cohort study of all Clalit Health Services members with hepatitis C virus genotype 1 who were dispensed dasabuvir/ombitasvir/paritaprevir/ritonavir from January 1, 2015 to-November 31, 2015. Results There were 564 participants during the study period. The average age was 61.9 years, 52.0% were male, and 61.5% were born Eastern/Central Europe or Central Asia. The prevalence of diabetes was 31.7% and 70.3% were overweight/obese. Cirrhosis was present in 41.0% of participants, of whom 52.8% had stage 4 fibrosis. Of the cohort, 416 (74.8%) had follow-up viral load testing at 10 or more weeks after the end of treatment. We report a sustained virological response of 98.8% among those tested. Conclusions Treatment with dasabuvir/ombitasvir/paritaprevir/ritonavir demonstrated a near universal effectiveness in achieving a sustained virological response among HCV patients in a large cohort.

Feasibility of multiple breath washout measurements in infants with bronchiolitis: A pilot study: Multiple Breath Washout in Bronchiolitis

Lung clearance index (LCI) reflects ventilation inhomogeneity and is raised in obstructive airway disease. Feasibility of multiple breath washout (MBW) measurement during acute lung disease in infants is unknown. As a further measure of disease, exhaled nitric oxide (eNO) may paradoxically decrease in acute bronchiolitis. We hypothesized that MBW measurements were attainable in infants with bronchiolitis and that LCI was raised and eNO reduced, compared to normal controls.

Estimated glomerular filtration rate within the normal or mildly impaired range and incident non-valvular atrial fibrillation: Results from a population-based cohort study

Background Lower estimated glomerular filtration rate, in particular in the significant renal impairment range (estimated glomerular filtration rate <60 ml/min/1.73 m2), is associated with incident atrial fibrillation. This association is less established within the normal or mildly impaired estimated glomerular filtration rate range. Methods Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate formula, we identified ambulatory adults (>22 years old) without rheumatic heart disease or prosthetic valves and with 60 ml/min/1.73 m2<estimated glomerular filtration rate<130 ml/min/1.73 m2 in their index visit, for incident, newly-diagnosed atrial fibrillation. We analyzed cohorts with and without prior cardiovascular disease. Results Over a mean follow-up of 104 months and >10 m patient-years of follow-up (∼75% <60 years old, ∼57% females), >65,000 individuals had ≥1 atrial fibrillation event (incident atrial fibrillation rate 5.1% and 5.8% excluding or including prior cardiovascular disease, or 49 and 55 per 10,000 patient-years, respectively). In both cohorts, individuals with versus without incident atrial fibrillation had lower mean estimated glomerular filtration rate (∼83 versus 95 ml/min/1.73 m2). Adjusting for age, gender, hypertension, and diabetes mellitus, overall a 10 ml/min/1.73 m2 decrease in estimated glomerular filtration rate was independently associated with a mean increase in incident atrial fibrillation of 1.5% and 2.4% in the cohorts excluding or including prior cardiovascular disease, respectively (p < 0.001 for both). However, a graded association between lower estimated glomerular filtration rate and atrial fibrillation was observed in the 90–130 ml/min/1.73 m2 range, whereas a blunted association was observed in the 60–90 ml/min/1.73 m2 range. Conclusion Within the 60 ml/min/1.73 m2 < estimated glomerular filtration rate < 130 ml/min/1.73 m2 range, lower estimated glomerular filtration rate is independently associated with incident non-valvular atrial fibrillation in adults without prior atrial fibrillation, mainly attributed to a graded association within the 90–130 ml/min/1.73 m2 range.

The association between eGFR in the normal or mildly impaired range and incident cadiovascular disease: Age and sex analysis

BACKGROUND Worse renal function, even in the normal or mildly impaired range, is associated with incident cardiovascular disease (CVD). Whether this association exists in both sexes across all ages is not known. METHODS A population based cohort of individuals >22 years with no prior CVD and with an eGFR 60-130 ml/min/1.73 m2. eGFR was calculated using the CKD-EPI formula. Incident CVD was defined as either myocardial infarction, unstable angina pectoris, coronary revascularization, or cerebrovascular event. Incident CVD was examined separately in men and women in 3 age-groups (young, 22-40 years; middle-aged, 41-60 years; and elderly, ≥61 years), during a median follow-up of 96.0 months. RESULTS Among 1,341,400 individuals (57% women, mean age 49.2 ± 16.6 years), men had more incident CVD as compared to women (34,968 vs. 23,515 total incident CVD) in all age-groups (0.6% vs. 0.2% in young; 6.2% vs. 2.0% in middle-aged; 13.4% vs. 8.4% in elderly, respectively). After adjustment for CVD risk factors, an increment of 10 units in eGFR was independently associated with a decrease of 5.4%, 3.4% and 5.4% in incident CVD in young, middle-aged and elderly men (p < 0.001 for each) and a decrease of 6.3%, 3.4% and 6.8% in the same age-groups in women (p < 0.001 for each). There was no significant age-sex interaction in the association between eGFR and incident CVD. CONCLUSION Although incident CVD differs in men and women, as well as in different age-groups, a higher eGFR even in the normal or mildly impaired range is associated with lesser incident CVD in men and women of all ages.

Which patients with Type 2 diabetes will have greater compliance to participation in the Diabetes Conversation Map™ program? A retrospective cohort study

AIM To investigate the characteristics of participants in the Diabetes Conversation Map™ (Map™) program who had higher vs. lower compliance to the program, to determine if program tailoring and monitoring is needed among these groups. METHODS This was a retrospective cohort study of 8990 patients enrolled in the Map™ program (low compliance [attending 0-1 sessions, n = 2759] and high compliance [attending ≥2 sessions, n = 6231]). Socio-demographic, clinical, health behaviors, and healthcare utilization characteristics were extracted. Multivariable stepwise logistic regression was used as the analysis strategy. RESULTS Those who were of higher socio-economic status (OR = 1.567, 95%CI:1.317-1.865), who lived in urban area (OR = 1.501, 95%CI:1.254-1.798), with greater frequency of primary care visits (OR = 1.012, 95%CI:1.002-1.021), with medium (OR = 1.176, 95%CI:1.013-1.365) or high oral medication adherence (OR = 1.198, 95%CI:1.059-1.356), and with a greater frequency of blood glucose tests (OR = 1.102, 95%CI:1.033-1.175) had greater odds of being in the high compliance group. Conversely, those aged 35-44 (OR = 0.538, 95%CI:0.402-0.721) and 45-54 years (OR = 0.763, 95%CI:0.622-0.937), with longer Type 2 diabetes duration (OR = 0.980, 95%CI:0.967-0.993), with higher blood glucose levels (OR = 0.999, 95%CI:0.998-1.000), and current (OR = 0.659, 95%CI:0.569-0.762) or former smokers (OR = 0.831, 95%CI:0.737-0.938) had reduced odds for being in the higher compliance group. CONCLUSIONS Instructors in advance can target sub-groups to increase their attendance rates, and consequently improve their outcomes.

Development and validation of novel algorithms to identify patients with inflammatory bowel diseases in Israel: an epi-IIRN group study

Background Before embarking on administrative research, validated case ascertainment algorithms must be developed. We aimed at developing algorithms for identifying inflammatory bowel disease (IBD) patients, date of disease onset, and IBD type (Crohn’s disease [CD] vs ulcerative colitis [UC]) in the databases of the four Israeli Health Maintenance Organizations (HMOs) covering 98% of the population. Methods Algorithms were developed on 5,131 IBD patients and 2,072 controls, following independent chart review (60% CD and 39% UC). We reviewed 942 different combinations of clinical parameters aided by mathematical modeling. The algorithms were validated on an independent cohort of 160,000 random subjects. Results The combination of the following variables achieved the highest diagnostic accuracy: IBD-related codes, alone if more than five to six codes or combined with purchases of IBD-related medications (at least three purchases or ≥3 months from the first to last purchase) (sensitivity 89%, specificity 99%, positive predictive value [PPV] 92%, negative predictive value [NPV] 99%). A look-back period of 2–5 years (depending on the HMO) without IBD-related codes or medications best determined the date of diagnosis (sensitivity 83%, specificity 68%, PPV 82%, NPV 70%). IBD type was determined by the majority of CD/UC codes of the three recent contacts or the most recent when less than three contacts were recorded (sensitivity 92%, specificity 97%, PPV 97%, NPV 92%). Applying these algorithms, a total of 38,291 IBD patients were residing in Israel, corresponding to a prevalence rate of 459/100,000 (0.46%). Conclusion The application of the validated algorithms to Israel’s administrative databases will now create a large and accurate ongoing population-based cohort of IBD patients for future administrative studies.

Distinct Lipoprotein Curves in Normal Weight, Overweight, and Obese Children and Adolescents

Objectives: Pediatric lipoprotein curves are based on population-based samples. As obesity, may alter lipoprotein levels, cutoffs not adjusted for body mass index (BMI) are potentially inappropriate. We aimed to develop distinct serum lipid curves based on sex- and BMI-percentiles for children and adolescents. Methods: Cross-sectional analysis included all healthy children and adolescents (age range 2–17 years) with available serum lipid concentrations (n = 152,820 of approximately 1.2 million children and adolescents per study year). These children and adolescents were categorized according to sex- and age-stratified BMI-percentiles: 100,375 normal weight (5th–85th percentile), 26,028 overweight (85th–95th percentile) and 26,417 obese (≥95th percentile) individuals. Excluded were individuals with hyperlipidemia, gastrointestinal disease, thyroid disease and lipid-lowering medications. Lambda-Mu-Sigma, smoothed percentile lipid curves were computed. Results: Obese children had a lipid profile pattern throughout childhood and adolescence similar to that of normal weight subjects but with a significant upward shift in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TGs) and a downward shift in high-density lipoprotein-cholesterol (HDL-C). Obese boys had 13 mg/dL higher TC levels (P < 0.001), 11 mg/dL higher LDL-C levels, 15 mg/dL higher non-HDL-C levels, and 5 mg/dL lower HDL-C levels (P < 0.001). Obese girls had 6 mg/dL higher TC levels, 7 mg/dL higher LDL-C levels, 11 mg/dl higher non-HDL-C levels, and 6 mg/dL lower HDL-C levels (P < 0.001). Conclusions: Across a large, nationally representative cohort of children and adolescents, lipoprotein levels were found to vary in relation to weight status. On the basis of these findings, it is suggested that when evaluating the lipid profile in the pediatric population, in addition to sex-based curves, clinical decision making may require consideration of BMI-stratified curves.