The impact of feedback training on prediction of cancer clinical trial results.

INTRODUCTION: Funders must make difficult decisions about which squared treatments to prioritize for randomized trials. Earlier research suggests that experts have no ability to predict which treatments will vindicate their promise. We tested whether a brief training module could improve experts' trial predictions. METHODS: We randomized a sample of breast cancer and hematology-oncology experts to the presence or absence of a feedback training module where experts predicted outcomes for five recently completed randomized controlled trials and received feedback on accuracy. Experts then predicted primary outcome attainment for a sample of ongoing randomized controlled trials. Prediction skill was assessed by Brier scores, which measure the average deviation between their predictions and actual outcomes. Secondary outcomes were discrimination (ability to distinguish between positive and non-positive trials) and calibration (higher predictions reflecting higher probability of trials being positive). RESULTS: A total of 148 experts (46 for breast cancer, 54 for leukemia, and 48 for lymphoma) were randomized between May and December 2017 and included in the analysis (1217 forecasts for 25 trials). Feedback did not improve prediction skill (mean Brier score for control: 0.22, 95% confidence interval = 0.20-0.24 vs feedback arm: 0.21, 95% confidence interval = 0.20-0.23; p = 0.51). Control and feedback arms showed similar discrimination (area under the curve = 0.70 vs 0.73, p = 0.24) and calibration (calibration index = 0.01 vs 0.01, p = 0.81). However, experts in both arms offered predictions that were significantly more accurate than uninformative forecasts of 50% (Brier score = 0.25). DISCUSSION: A short training module did not improve predictions for cancer trial results. However, expert communities showed unexpected ability to anticipate positive trials.Pre-registration record: https://aspredicted.org/4ka6r.pdf.

The proportion of North American cancer trials that evaluate novel targets.

Major advances in cancer care often emerge from the development of novel targets. We randomly sampled 10% of cancer trials on clinicaltrials.gov with start dates 2013-2016 to determine the proportion of trials and research subjects directed at evaluating novel targets. We found that 87 of 378 trials (23.0%) enrolling 9225 of 44,525 patients (20.7%) tested interventions that are directed towards novel targets. 146 of 378 trials (38.6%) enrolling 19,132 of 44,525 patients (43.0%) investigated treatments that were not FDA approved but utilized a previously studied target for treating cancer. Combined, 233 of 378 trials (61.6%) enrolling 28,357 of 44,525 patients (63.9%) investigated treatments that were not FDA approved. Furthermore, 36 of 378 trials (9.5%) enrolling 6592 of 44,525 patients (14.8%) investigated FDA approved anticancer drugs in their approved indication and combination while 109 of 378 trials (28.8%) enrolling 9576 of 44,525 patients (21.5%) investigated FDA approved anticancer drugs outside of their approved indication or combination. Logistic regression found that phase 1 trials were significantly more likely to test novel target interventions than phase 2 and 3 trials (p value = 0.00197 and 0.00130 respectively). Industry sponsored trials were also significantly more likely to involve novel target interventions than non-industry trials (p value <0.001). In conclusion, most cancer trials involve unapproved treatments, but a majority of these treatments are well-characterized or involve a previously studied target to treat cancer.

Risks and benefits of unapproved disease-modifying treatments for neurodegenerative disease.

OBJECTIVE: To determine whether patients randomized to unapproved, disease-modifying interventions in neurodegenerative disease trials have better outcomes than patients randomized to placebo by performing a systematic review and meta-analysis of risk and benefit experienced by patients in randomized placebo-controlled trials testing investigational treatments for Alzheimer disease, Parkinson disease, Huntington disease, or amyotrophic lateral sclerosis (ALS). METHODS: We searched MEDLINE, Embase, and ClinicalTrials.gov for results of randomized trials testing non-Food and Drug Administration-approved, putatively disease-modifying interventions from January 2005 to May 2018. Trial characteristics were double-extracted. Coprimary endpoints were the treatment advantage over placebo on efficacy (standardized mean difference in outcomes) and safety (risk ratios of serious adverse events and withdrawals due to adverse events), calculated with random effects meta-analyses. The study was registered on PROSPERO (CRD42018103798). RESULTS: We included 113 trials (n = 39,875 patients). There was no significant efficacy advantage associated with assignment to putatively disease-modifying interventions compared to placebo for Alzheimer disease (standardized mean difference [SMD] -0.03, 95% confidence interval [CI] -0.07 to 0.01), Parkinson disease (SMD -0.09, 95% CI -0.32 to 0.15), ALS (SMD 0.02, 95% CI -0.25 to 0.30), or Huntington disease (0.02, 95% CI -0.27 to 0.31). Patients with Alzheimer disease assigned to active treatment were at higher risk of experiencing serious adverse events (risk ratio [RR] 1.15, 95% CI 1.04-1.27) and withdrawals due to adverse events (RR 1.44, 95% CI 1.21-1.70). CONCLUSIONS: Assignment to active treatment was not beneficial for any of the indications examined and may have been slightly disadvantageous for patients with Alzheimer disease. Our findings suggest that patients with neurodegenerative diseases are not, on the whole, harmed by assignment to placebo when participating in trials.

Important role of hepatitis C virus infection as a cause of chronic liver disease in Somalia.

In a case-control study, 62 Somali patients with chronic liver disease (CLD) including primary hepatocellular carcinoma (HCC) and the same number of age and sex matched controls were investigated for serological markers of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. Antibody to HCV (anti-HCV) was detected in 40.3% and 6.5% of cases and controls, respectively. The corresponding prevalences of hepatitis B surface antigen (HBsAg) were 37.1% and 9.7%, respectively. Of the HBsAg-positive cases, 34.6% had antibodies to hepatitis D virus (anti-HD) compared with 14.3% among the HBsAg-positive controls. Anti-HCV was less prevalent in HBsAg-positive cases than among HBsAg-negative patients (p < 0.001), indicating that these agents were independent causes of CLD/HCC. The odds ratios for patients with CLD/HCC associated with the presence of anti-HCV, anti-HD, HBsAg without anti-HD and anti-HCV, were found to be 9.8, 10.4, and 3.3, respectively. When the patients were divided into tumour and non-tumour cases, using the criteria of serum alpha-fetoprotein > 100 ng/ml and/or solid hepatic lesions detected by ultrasonography, they did not differ with regard to frequencies of HBsAg and/or anti-HCV, although they did differ when these markers were taken together (43/49 versus 5/13, respectively). The mean age of the tumour patients with anti-HCV alone was significantly higher than that of tumour patients with HBsAg as the sole marker, 61.7 versus 31.4 years (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The Omaha System. A research-based model for decision making.

This article describes the value, diversity, and potential benefits of the Omaha System in generalizing and manipulating client, clinical, and financial data. The authors provide examples of its utility for day-to-day and long-range clinical and financial decision making in home and public health agencies, colleges of nursing, and ambulatory care centers throughout the United States and Canada.

The risk for hepatitis A, B, and C at two institutions for children in Somalia with different socioeconomic conditions.

The prevalence of serologic markers for hepatitis A, B, and C was investigated in children from two residential institutions in Somalia. Among 596 individuals at one residence (Shebeli), the prevalences were 96% for antibody to hepatitis A virus (anti-HAV), 75% for total hepatitis B virus (HBV) markers, 16% for hepatitis B surface antigen (HBsAg), and 1.5% for antibody to hepatitis C virus (anti-HCV). Corresponding figures for the 76 individuals at a smaller residence (Societe Organisation Sociale, SOS) were 59%, 20%, 3.9%, and 0%, respectively. At Shebeli, the HBsAg carrier rates in the 1-10-year-old age group was 28% for boys and 16% for girls. These rates were significantly higher than in the older children (16% and 7.4% for boys and girls, respectively). Fifty-eight percent of the HBsAg carriers were positive for hepatitis B e antigen. Total HBV markers were significantly more frequent in girls from Shebeli, when their duration of residence was longer than five years (89% versus 63%). The duration of stay did not influence the prevalences of HBsAg, HAV, or HCV antibodies. A followup study of children initially seronegative for HBV markers was carried out after two years. For children at Shebeli 1-10 years old, the annual seroconversion rates to HBV markers (95% confidence interval) was 60.5% (42.7-77.0%). The corresponding rate for children at SOS was 10.2% (5.2-17.5%). The differences between the two institutions in the prevalence of serologic markers for hepatitis A and B, and in the annual seroconversion rate to HBV markers reflected different rates of horizontal transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Late seroconversion to hepatitis B in a Somali village indicates the important role of venereal transmission.

Hepatitis B virus (HBV) markers were investigated in a cross-sectional study in 1985 on sera from 84% of the 648 inhabitants in a rural Somali village. The prevalence of HBV markers increased with age, from 9.7% in subjects less than 12 years old, to 38% in the age group 12-19 years, and to 68% in adults. HBV markers were more common in boys less than 12 years old, 13%, than in girls of the same age group, 5.8% (P less than 0.05). A rapid increase of HBV markers started at adolescence in both sexes. The female cohort showed their highest seroconversion rate during their second decade of life, while the male cohort seroconverted more rapidly in the third decade. Thus, an initially more rapid seroconversion among boys was reversed when the females reached reproductive age, and no sex difference in marker frequencies was observed in the age group 12-19 years. There was a steady increase of HBV markers during the reproductive years in both sexes. The frequencies of HBsAg, as well as total markers, were significantly higher in adult males than females, 14 vs 5.6%, and 77 vs 62%, respectively. HBV markers were more frequent in wives of HBV positive husbands than in those married to HBV negative husbands. No increased marker prevalence was observed among siblings of HBV positive children, nor among their mothers, which disproved the role of vertical and early horizontal transmission. In 1989 the four-year rate of seroconversion was investigated in villagers who were seronegative in 1985. On testing 158 sera from 319 individuals, the seroconversion rate was significantly lower among those younger than 12 years in 1985 compared to those in the older age group, 5 vs 17%.(ABSTRACT TRUNCATED AT 250 WORDS)

Minor role of hepatitis B virus in the causation of chronic liver disease in Somalia indicated by a case-control study.

Chronic liver disease (CLD) is frequent in Somalia. In a case-control study, 116 in-patients with CLD were compared with the same number of age and sex matched controls. Demographic variables, use of drugs, symptoms and signs, serological markers for hepatitis B virus (HBV) and serum alpha-foetoprotein (AFP) were assessed. Hepatitis B surface antigen (HBsAg) was found in 44 cases of which 17 had antibodies to hepatitis D virus (anti-HD) and 7 had hepatitis B e antigen (HBeAg). Twenty-three controls were HBsAg-positive, of whom 3 had anti-HD and one HBeAg. Increased relative risks (95% confidence intervals in parentheses) were 2.5 (1.3-4.5) for HBsAg, 6.5 (1.7-21.5) for anti-HD, and 7.4 (0.9-66.5) for HBeAg. Despite the association between the presence of HBV markers and CLD, 62% of the cases had no markers indicating current HBV infection. This was reflected in the low risk attributable to chronic HBV infection (22.6%), which was lower than that in patients with CLD in other African populations with a high HBsAg carrier rate. The prevalence of HBV markers did not differ between cases with AFP greater than 100 ng/ml and those with AFP less than 100 ng/ml. The former were characterized by male predominance, shorter duration of symptoms, and larger mean liver size, indicative of malignancy. The mean age of HBsAg-positive cases with AFP greater than 100 ng/ml was significantly lower (by 7.7 years) than that of HBsAg-negative cases with AFP greater than 100 ng/ml. Among the CLD patients with AFP less than 100 ng/ml, 48 were HBsAg-negative. These cases differed significantly from the other 68 cases in that more were females (35% against 16%), more originated from an agricultural area (56% against 30%), and more were regular consumers of drugs (48% against 28%). In conclusion, factors as yet undefined play a considerable role in the causation of CLD in Somalia. The possibility of determining the role of hepatitis C virus (HCV) awaits the development of more specific assays for anti-HCV antibodies.

Tumorigenicity of mouse-human diploid hybrids in nude mice.

Somatic cell hybrids between normal mouse cells and simian virus 40 (SV40)-transformed human cells, which contained a diploid complement of mouse chromosomes and the human chromosome 7 carrying the genome of SV40, were tumorigenic in nude mice. One single copy of human chromosome 7 per hybrid cell appeared to be sufficient for the tumorigenicity of the hybrids.