Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models

Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model’s structure and in silico “experimental” data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation

VAT compliance, trade, and institutions

We develop a simple model of value added tax (VAT) compliance, and estimate it using widely available national accounts data to learn about compliance in countries where little is currently known. International border controls improve VAT compliance, generating a correlation between imports and aggregate VAT revenues that is informative about domestic noncompliance. Estimates suggest that revenue lost due to domestic non-compliance is large, particularly in countries with low perceived institutional quality. We analyze how our estimates are related to institutional differences among countries, and discuss the implications for tax polic

Predicting outcome in hyper-acute stroke: validation of a prognostic model in the Third International Stroke Trial (IST3)

Background and purpose: Models are used to adjust for case mix and to stratify treatment allocation in clinical trials and can, if accurate enough, be used to aid decision-making in individual patients. We aimed to validate, in patients assessed within 6 hours of onset, a previously described six simple variable (SSV) model that was developed in stroke patients who were assessed sub-acutely. The explanatory variables in the model are age, living alone, independent pre-stroke, Glasgow Coma Scale verbal score, ability to lift arms and ability to walk. Methods: The six variables were collected at randomisation in the Third International Stroke Trial (IST3) trial of recombinant tissue plasminogen activator in ischaemic stroke. We assessed survival to 30 days and functional status at 6 months using the Oxford Handicap Scale. We constructed receiver operator characteristic (ROC) curves to establish the model's discriminatory performance and tested its calibration by charting predicted versus actual outcomes. Results: 537 patients (mean age, 74 years) were included, of whom 422 (79%) survived 30 days and 179 (33%) were alive and independent at 6 months. The SSV model had an area under the ROC curve of 0.73 for 30-day survival and 0.82 for independent survival at 6 months. Calibration was satisfactory. Conclusions: This study confirms the external validity of the SSV model in an ischaemic stroke population assessed within 6 hours of symptom onset. The SSV model comprising easily collected variables can therefore be used to stratify patients in hyper-acute stroke trials, but probably is not accurate enough for decision-making in individual patients

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

Background Intravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit. Design International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics. Results The initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials. Conclusion The data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials

The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial

Background Thrombolysis is of net benefi t in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefi t up to 6 h from stroke onset. Methods In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defi ned by an Oxford Handicap Score (OHS) of 0–2 at 6 months. The study is registered, ISRCTN25765518. Findings 3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0–2; adjusted odds ratio [OR] 1·13, 95% CI 0·95–1·35, p=0·181; a non-signifi cant absolute increase of 14/1000, 95% CI –20 to 48). An ordinal analysis showed a signifi cant shift in OHS scores; common OR 1·27 (95% CI 1·10–1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07–11·8; absolute excess 58/1000, 95% CI 44–72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22–2·08, p=0·001; absolute increase 37/1000, 95% CI 17–57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group)