Statistical controversies in clinical research: Value of adverse events relatedness to study treatment: analyses of data from randomized double-blind placebo-controlled clinical trials.

BACKGROUND: Collection and reporting of adverse events (AEs) and their relatedness to study treatment, known commonly as attribution, in clinical trials is mandated by regulatory agencies (the National Cancer Institute and the Food and Drug Administration). Attribution is assigned by the treating physician using judgment based on various factors including patient's baseline status, disease history, and comorbidity as well as knowledge about the safety profile of the study treatments. We evaluate the patterns of AE attribution (unrelated, unlikely, possibly, probably, and definitely related to the treatment) in treatment, symptom intervention (cancer patients) and cancer prevention (participants at high risk for cancer) setting. MATERIALS AND METHODS: Nine multicenter placebo-controlled trials (two treatment, two symptom intervention, and five cancer prevention) were analysed separately (2155 patients). Frequency and severity of AEs were summarized by arm. Attribution and percentage of repeated AEs whose attribution changed overtime were summarized for the placebo arms. Percentage of physician over- or under-reporting of AE relatedness was calculated for the treatment arms using the placebo arm as the reference. RESULTS: Across all trials and settings, a very high proportion of AEs reported as related to treatment were classified as possibly related, a significant proportion of AEs in the placebo arm were incorrectly reported as related to treatment, and clinician-reported attribution over-estimated the rate of AEs related to treatment. Fatigue, nausea, vomiting, diarrhea, constipation, and neurosensory were the common AEs that were over reported by clinician as related to treatment. CONCLUSIONS: These analyses demonstrate that assigning causality to AE is a complex and difficult process that produces unreliable and subjective data. In randomized double-blind placebo-controlled trials where data are available to objectively assess relatedness of AE to treatment, attribution assignment should be eliminated.

Delivery of small-for-gestational-age neonate and association with early-onset impaired maternal endothelial function.

OBJECTIVE: Women who have delivered a small-for-gestational-age (SGA) infant are at an increased risk of developing cardiovascular disease (CVD) in later life. Endothelial dysfunction is a subclinical sign of early CVD. It is unknown whether women who have recently had a pregnancy complicated by SGA, in the absence of other maternal and fetal diseases, have subclinical endothelial dysfunction. Our aim was to assess maternal endothelial function 6 months after a pregnancy complicated by SGA. METHODS: This was a case-control study conducted in a tertiary referral hospital in London, UK, over a 15-month period. Flow-mediated dilatation (FMD) of the brachial artery was measured in women 6.9 ± 2.5 months after childbirth. Forty-four women were included in the study, of whom 15 had a SGA neonate (mean ± SD customized birth centile of 1.9 ± 2.3) and 29 delivered an appropriately grown baby (mean ± SD customized birth centile of 47.5 ± 26.3). The primary continuous variable, FMD, was assessed in each group and compared using unpaired t-test. RESULTS: Women who had a SGA neonate had lower postpartum FMD (6.79 ± 0.95%) than did those who had an appropriately grown offspring (10.26 ± 2.44% (95% CI for difference between groups, -5.37 to -1.57); P = 0.0007). There were no differences in postnatal maternal blood pressure, abdominal circumference, weight and glucose, insulin and lipid profiles between the two groups. CONCLUSIONS: Women who had a pregnancy affected by SGA, probably due to placental failure in the absence of pre-eclampsia, have evidence of subclinical endothelial dysfunction within 6 months of childbirth. These women may benefit from lifestyle measures focused on the primary prevention of CVD. Further research in larger populations is needed to ascertain if such postpartum maternal endothelial dysfunction is a pregnancy-induced phenomenon or if it is related to the pre-existing maternal phenotype, and whether it persists long term. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Comparison of Solomon technique with selective laser ablation for twin-twin transfusion syndrome: a systematic review.

OBJECTIVE: To compare the Solomon and selective techniques for fetoscopic laser ablation (FLA) for the treatment of twin-twin transfusion syndrome (TTTS) in monochorionic-diamniotic twin pregnancies. METHODS: This was a systematic review conducted in accordance with the PRISMA statement. Electronic searches were performed for relevant citations published from inception to September 2014. Selected studies included pregnancies undergoing FLA for TTTS that reported on recurrence of TTTS, occurrence of twin anemia-polycythemia sequence (TAPS) or survival. RESULTS: From 270 possible citations, three studies were included, two cohort studies and one randomized controlled trial (RCT), which directly compared the Solomon and selective techniques for FLA. The odds ratios (OR) of recurrent TTTS when using the Solomon vs the selective technique in the two cohort studies (n = 249) were 0.30 (95% CI, 0.00-4.46) and 0.45 (95% CI, 0.07-2.20). The RCT (n = 274) demonstrated a statistically significant reduction in risk of recurrent TTTS with the Solomon technique (OR, 0.21 (95% CI, 0.04-0.98); P = 0.03). The ORs for the development of TAPS following the Solomon and the selective techniques were 0.20 (95% CI, 0.00-2.46) and 0.61 (95% CI, 0.05-5.53) in the cohort studies and 0.16 (95% CI, 0.05-0.49) in the RCT, with statistically significant differences for the RCT only (P < 0.001). Observational evidence suggested overall better survival with the Solomon technique, which was statistically significant for survival of at least one twin. The RCT did not demonstrate a significant difference in survival between the two techniques, most probably owing to the small sample size and lack of power. CONCLUSION: This systematic review of observational, comparative cohort and RCT data suggests a trend towards a reduction in TAPS and recurrent TTTS and an increase in twin survival, with no increase in the occurrence of complications or adverse events, when using the Solomon compared to the selective technique for the treatment of TTTS. These findings need to be confirmed by an appropriately-powered RCT with long-term neurological follow-up.

Additional information from chromosomal microarray analysis (CMA) over conventional karyotyping when diagnosing chromosomal abnormalities in miscarriage: a systematic review and meta-analysis.

BACKGROUND: Approximately 50% of spontaneous miscarriages are associated with chromosome abnormalities. Identification of these karyotypic abnormalities helps to estimate recurrence risks in future pregnancies. Chromosomal microarray analysis (CMA) is transforming clinical cytogenetic practice with its ability to examine the human genome at increasingly high resolution. OBJECTIVES: The aim of this study was to determine whether CMA testing on the products of conception following miscarriage provides better diagnostic information compared with conventional karyotyping. SEARCH STRATEGY: MEDLINE (from 1996 to December 2012), EMBASE (from 1974 to December 2012), and CINAHL (from 1996 to December 2012) databases were searched electronically. SELECTION CRITERIA: Studies were selected if CMA was used on products of conception following miscarriage, alongside conventional karyotyping. DATA COLLECTION AND ANALYSIS: Nine papers were included in the systematic review and meta-analysis. All statistical analyses were performed using stata 11.0 (Stata Corp., College Station, TX, USA). MAIN RESULTS: There was agreement between CMA and karyotyping in 86.0% of cases (95% CI 77.0-96.0%). CMA detected 13% (95% CI 8.0-21.0) additional chromosome abnormalities over conventional full karyotyping. In addition, traditional, full karyotyping detected 3% (95% CI 1.0-10.0%) additional abnormalities over CMA. The incidence of a variant of unknown significance (VOUS) being detected was 2% (95% CI 1.0-10.0%). AUTHOR'S CONCLUSIONS: Compared with karyotyping, there appears to be an increased detection rate of chromosomal abnormalities when CMA is used to analyse the products of conception; however, some of these abnormalities are VOUS, and this information should be provided when counselling women following miscarriage and when taking consent for the analysis of miscarriage products by CMA.

Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis.

OBJECTIVES: Chromosomal microarray analysis (CMA) is utilized in prenatal diagnosis to detect chromosomal abnormalities not visible by conventional karyotyping. A prospective cohort of women undergoing fetal CMA and karyotyping following abnormal prenatal ultrasound findings is presented in the context of a systematic review and meta-analysis of the literature describing detection rates by CMA and karyotyping. METHODS: We performed a prospective cohort study of 243 women undergoing CMA alongside karyotyping when a structural abnormality was detected on prenatal ultrasound. A systematic review of the literature was also performed. MEDLINE (1970-Dec 2012), EMBASE (1980-Dec 2012) and CINAHL (1982-June 2012) databases were searched electronically. Selected studies included > 10 cases and prenatal CMA in addition to karyotyping. The search yielded 560 citations. Full papers were retrieved for 86, and 25 primary studies were included in the systematic review. RESULTS: Our cohort study found an excess detection rate of abnormalities by CMA of 4.1% over conventional karyotyping when the clinical indication for testing was an abnormal fetal ultrasound finding; this was lower than the detection rate of 10% (95% CI, 8-13%) by meta-analysis. The rate of detection for variants of unknown significance (VOUS) was 2.1% (95% CI, 1.3-3.3%) when the indication for CMA was an abnormal scan finding. The VOUS detection rate was lower (1.4%; 95% CI, 0.5-3.7%) when any indication for prenatal CMA was meta-analyzed. CONCLUSION: We present evidence for a higher detection rate by CMA than by karyotyping not just in the case of abnormal ultrasound findings but also in cases of other indications for invasive testing. It is likely that CMA will replace karyotyping in high-risk pregnancies.

Physicochemical and toxicological profiling of ash from the 2010 and 2011 eruptions of Eyjafjallajökull and Grímsvötn volcanoes, Iceland using a rapid respiratory hazard assessment protocol.

The six week eruption of Eyjafjallajökull volcano in 2010 produced heavy ash fall in a sparsely populated area of southern and south eastern Iceland and disrupted European commercial flights for at least 6 days. We adopted a protocol for the rapid analysis of volcanic ash particles, for the purpose of informing respiratory health risk assessments. Ash collected from deposits underwent a multi-laboratory physicochemical and toxicological investigation of their mineralogical parameters associated with bio-reactivity, and selected in vitro toxicology assays related to pulmonary inflammatory responses. Ash from the eruption of Grímsvötn, Iceland, in 2011 was also studied. The results were benchmarked against ash from Soufrière Hills volcano, Montserrat, which has been extensively studied since the onset of eruptive activity in 1995. For Eyjafjallajökull, the grain size distributions were variable: 2-13 vol% of the bulk samples were <4 µm, with the most explosive phases of the eruption generating abundant respirable particulate matter. In contrast, the Grímsvötn ash was almost uniformly coarse (<3.5 vol%<4 µm material). Surface area ranged from 0.3 to 7.7 m2 g(-1) for Eyjafjallajökull but was very low for Grímsvötn (<0.6 m2 g(-1)). There were few fibre-like particles (which were unrelated to asbestos) and the crystalline silica content was negligible in both eruptions, whereas Soufrière Hills ash was cristobalite-rich with a known potential to cause silicosis. All samples displayed a low ability to deplete lung antioxidant defences, showed little haemolysis and low acute cytotoxicity in human alveolar type-1 like epithelial cells (TT1). However, cell-free tests showed substantial hydroxyl radical generation in the presence of hydrogen peroxide for Grímsvötn samples, as expected for basaltic, Fe-rich ash. Cellular mediators MCP-1, IL-6, and IL-8 showed chronic pro-inflammatory responses in Eyjafjallajökull, Grímsvötn and Soufrière Hills samples, despite substantial differences in the sample mineralogy and eruptive styles. The value of the pro-inflammatory profiles in differentiating the potential respiratory health hazard of volcanic ashes remains uncertain in a protocol designed to inform public health risk assessment, and further research on their role in volcanic crises is warranted.

Microarray comparative genomic hybridization in prenatal diagnosis: a review.

G-band chromosomal karyotyping of fetal cells obtained by invasive prenatal testing has been used since the 1960s to identify structural chromosomal anomalies. Prenatal testing is usually performed in response to parental request, increased risk of fetal chromosomal abnormality associated with advanced maternal age, a high-risk screening test and/or the presence of a congenital malformation identified by ultrasonography. The results of karyotyping may inform the long-term prognosis (e.g. aneuploidy being associated with a poor outcome or microscopic chromosomal anomalies predicting global neurodevelopmental morbidity). Relatively recent advances in microarray technology are now enabling high-resolution genome-wide evaluation for DNA copy number abnormalities (e.g. deletions or duplications). While such technological advances promise increased sensitivity and specificity they can also pose difficult challenges of interpretation and clinical management. This review aims to give interested clinicians without an extensive prior knowledge of microarray technology, an overview of its use in prenatal diagnosis, the literature to date, advantages, potential pitfalls and experience from our own tertiary center.

Advancing our understanding of skeletal muscle across the lifecourse: Protocol for the MASS_Lifecourse study and characteristics of the first 80 participants.

INTRODUCTION: Sarcopenia, the age-related loss of skeletal muscle strength and mass, carries a significant burden for affected individuals. There has been little investigation of sarcopenia using experimental medicine techniques to study human muscle tissue in detail. The aim of the Muscle Ageing Sarcopenia Studies Lifecourse (MASS_Lifecourse) study is to recruit up to 160 participants, equally divided between females and males between ages 45 and 85 years for detailed phenotyping of skeletal muscle health. Here we describe the protocol for the study and the characteristics of the first 80 participants. METHODS: We are recruiting participants from three sources in the north-east of England. Study fieldwork comprises a home visit (or videocall) for consent and assessment of health, cognition, lifestyle, and wellbeing. This is followed by a visit to a clinical research facility for assessment of sarcopenia status and collection of samples including a vastus lateralis muscle biopsy. We produced descriptive statistics for the first 80 participants, including expressing their grip strength relative to normative data in the form of Z-scores. RESULTS: The first 80 participants (53.8 % female) covered the target ages, ranging from 48 to 84 years. They were regularly physically active, reported good physical function and had a prevalence of sarcopenia (including probable sarcopenia) of 11.3 % based on the revised European consensus. Their grip strength was similar to that in the general population, with a mean Z-score of 0.09 standard deviations (95 % CI: -1.64, 1.83) above that expected. CONCLUSIONS: The MASS_Lifecourse study combines comprehensive health and lifestyle data with a range of biological samples including skeletal muscle. The findings from planned analyses should contribute to improvements in the diagnosis, treatment, and prevention of sarcopenia.

Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis.

OBJECTIVE: Array comparative genomic hybridization (CGH) is transforming clinical cytogenetics with its ability to interrogate the human genome at increasingly high resolution. The aim of this study was to determine whether array CGH testing in the prenatal population provides diagnostic information over conventional karyotyping. METHODS: MEDLINE (1970 to December 2009), EMBASE (1980 to December 2009) and CINAHL (1982 to December 2009) databases were searched electronically. Studies were selected if array CGH was used on prenatal samples or if array CGH was used on postnatal samples following termination of pregnancy for structural abnormalities that were detected on an ultrasound scan. Of the 135 potential articles, 10 were included in this systematic review and eight were included in the meta-analysis. The pooled rate of extra information detected by array CGH when the prenatal karyotype was normal was meta-analyzed using a random-effects model. The pooled rate of receiving an array CGH result of unknown significance was also meta-analyzed. RESULTS: Array CGH detected 3.6% (95% CI, 1.5-8.5) additional genomic imbalances when conventional karyo-typing was 'normal', regardless of referral indication. This increased to 5.2% (95% CI, 1.9-13.9) more than karyotyping when the referral indication was a structural malformation on ultrasound. CONCLUSIONS: There appears to be an increased detection rate of chromosomal imbalances, compared with conventional karyotyping, when array CGH techniques are employed in the prenatal population. However, some are copy number imbalances that are not clinically significant. This carries implications for prenatal counseling and maternal anxiety.

Reliability and validity of the Edinburgh Visual Gait Score for cerebral palsy when used by inexperienced observers.

The Edinburgh Visual Gait Score (EVGS) for cerebral palsy has been validated for observer reliability and validity for observers experienced in gait analysis. This study investigated the reliability and validity of the EVGS for observers inexperienced in gait analysis. Six medical students used the score to analyse videotapes from the original study by Read et al. [Read HS, Hazlewood ME, Hillman SJ, Prescott RJ, Robb JE. Edinburgh visual gait score for use in cerebral palsy. J Pediatr Orthop 2003;23:296-301]. These were viewed on two separate occasions to provide inter- and intra-observer reliability, and the results of the numerical items were compared to those from three-dimensional (3D) gait analyses for validity. Observer agreement was tested using Coefficient of Repeatability (CoR), percentage of complete agreement and the kappa statistic. The CoR for inter-observer agreement for inexperienced observers was 5.99/5.07 (Session 1/Session 2) compared to 4.60/3.95 (Session 1/Session 2) for experienced observers. The CoR for intra-observer agreement for inexperienced observers was 5.15 compared to 4.21 for experienced observers. There was complete agreement for 52% of the 10 numerical items with 3D-gait analysis data for inexperienced observers compared to 64% for experienced observers. Ranking of reliability of individual items was similar between the two groups and was generally best for events occurring at the foot and ankle. Observations of gait events by the inexperienced observers using the EVGS were reasonably reliable but not very accurate when compared to experienced observers and 3D-gait analysis.

Reliability and validity of the Visual Gait Assessment Scale for children with hemiplegic cerebral palsy when used by experienced and inexperienced observers.

This study investigated the reliability and validity of the Visual Gait Assessment Scale when used by experienced and inexperienced observers. Four experienced and six inexperienced observers viewed videotaped footage of four children with hemiplegic cerebral palsy on two separate occasions. Validity of the Scale was obtained by comparison with three-dimensional gait analysis (3DGA). The experienced observers generally had higher inter-observer and intra-observer reliability than the inexperienced observers. Both groups showed higher agreement for assessments made at the ankle and foot than at the knee and hip. The experienced observers had slightly higher agreement with 3DGA than the inexperienced observers. The inexperienced observers showed a learning effect and had higher inter-observer agreement and higher agreement with 3DGA in the second assessment of the videotapes. This scale can be used by inexperienced observers but is limited to observations in the sagittal plane and by poor reliability at the knee and hip for experienced and inexperienced observers.

The effect of simulated hamstring shortening on gait in normal subjects.

The purpose of this study was to determine the effect of simulated hamstring shortening on gait in normal subjects. Six normal subjects wore an adjustable brace to simulate three different hamstring lengths. Evaluation of the physiological cost index (PCI) and gait analysis revealed that simulated hamstring shortening produced adverse affects in the gait of normal subjects. Significant effects were only observed when the popliteal angle exceeded 85 degrees (p<0.001) and included increased effort of walking (PCI), decreased speed, stride and step length; decreased hip flexion and increased knee flexion in stance, increased posterior pelvic tilt, decreased pelvic obliquity and rotation and premature ankle dorsi- and plantar-flexion in stance. These results emphasise the need to consider the effects of changing the length of the hamstrings on joints other than the hip and knee when assessing patients for hamstring lengthening.

The Footprint method to assess transmalleolar axis.

Torsional deformities of the lower extremities are a common reason for an orthopaedic consultation and are also part of the evaluation of a patient in gait analysis. This study assessed the level of agreement between, and the repeatability of, the Footprint method and two other methods (Prone and Jig) of measuring the transmalleolar axis (TMA) clinically. The Footprint method measures the TMA as the patient sits by projecting the position of the malleoli downwards onto lined paper while the lines of the paper are aligned with the knee axis. The Prone method projects the position of the malleoli upwards onto the sole of the foot and this is related to the visually estimated knee axis. The Jig method uses a tropometer to relate the angle between the tibial tubercle and the two malleoli. Two assessors measured twelve subjects using the three methods and six subjects were re-measured approximately 1 week later for repeatability. There was poor agreement between the three methods but the Footprint method was the most repeatable (coefficient of repeatability: 5.4). One observer then assessed the repeatability of the effect of simulated equinus on the Footprint method in 10 normal subjects on 2 separate occasions 1 week apart. Equinus was obtained by having the subjects sit and firstly extend their knee and place the foot on the floor and secondly by placing the foot under consideration on a wedge. Both conditions introduced an offset into the measurement of the TMA when compared to the measurements with the ankle at neutral in the same subjects. The reliability of the Footprint method was then assessed using 10 inexperienced observers who measured nine normal subjects each on 2 separate occasions and their results compared with those from an experienced observer. The inexperienced observers were less repeatable than an experienced observer (coefficients of repeatability 9.2 and 6.9, respectively). We recommend that different methods of measuring TMA should not be used interchangeably in clinical practice. The Footprint method was the most repeatable of the three methods tested and can be used for patients who have fixed equinus but the measurement was less repeatable when used by inexperienced observers.

Regression analysis of gait parameters with speed in normal children walking at self-selected speeds.

Dimensionless analysis ensures that differences in sizes (e.g. height and weight) of children have a minimal influence on gait parameters. The results of changes in speed on gait parameters were examined using dimensionless analysis on data from a prospective 5-year study of 16 children. Linear regression analysis of peak and trough values of temporal distance parameters, ground reaction forces, joint angles, moments and powers provide a quantitative description of gait development with normalised speed. These linear relationships can be used to estimate gait parameters from speed measurements for normal subjects. However, caution is advised in using the data to attempt to predict an individual's gait parameters due to the wide spread of data about the regression lines and we do not recommend that the data be used to extrapolate the regression data to wider speed ranges.

Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma.

PURPOSE: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial. PATIENTS AND METHODS: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response. RESULTS: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (> or = grade 3) than those who received ODTI (12.3% v 5.3%; P =.05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation. CONCLUSION: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.