The development and application of novel intelligent scoring systems in critical illness

Scoring systems in medicine are not a new concept. There are examples from the early 1950s, from around the same time as the polio epidemic in Copenhagen resulted in the birth of modern Intensive Care. Many scores have subsequently been developed specifically for Intensive Care patients. The majority summarise the overall physiological state of the patient in a variety of different ways. A clinical interest in ascertaining whether haemodialysis causes cardiovascular instability in Intensive Care patients led to an initial simple experiment examining stability using a small number of cardiovascular parameters. It became apparent that to answer the question properly a physiologically based score which could be calculated automatically in real time, and which took into account the level of physiological or pharmacological support the patient was receiving would have to be developed, to counter or to mitigate the drawbacks of the main scoring systems in common use at the time. This thesis describes the development and first stage in the validation of a novel physiologically based scoring system for Intensive Care patients which overcomes some of the major disadvantages of existing scores. The score was then used to investigate other clinical questions. Myocardial damage in Intensive Care is common and associated with a poor outcome. Aspects of the developed score were used to ascertain if it is possible to detect and predict myocardial damage occurring in Intensive Care patients based on physiological disturbance rather than a rise in biomarkers. The score was subsequently used to examine Intensive Care patient outcomes. The introductory chapter describes the history of Intensive Care, the mechanism of data collection for patients in Scottish Intensive Care Units and its analysis to enable comparison of different units. Reviewing currently available scoring systems places this work in context and highlights the need for a new score. An overview of renal replacement therapy modalities follows, as an interest in cardiovascular stability during haemodialysis led to the idea for a new scoring system. Myocardial damage in Intensive Care patients is common and indicative of poorer outcomes. This is reviewed, as the developed score was used to detect and then predict where myocardial damage was occurring in critically ill patients, based on physiological disturbance rather than on raised biomarkers. In Chapter 2, data from dialysis sessions in critically ill patients was collected, prc-processed, and analysed for cardiovascular instability. Using an arbitrary definition of instability as a 20% change in mean arterial pressure or heart rate in either direction, 65% of dialysis sessions were stable and 35% unstable. This simple experiment suggested that haemodialysis is less cardiovascularly destabilising than previously believed. However a major deficiency was the lack of consideration of the level of physiological support required during dialysis. To investigate this and other clinical problems better, it became apparent that a new score would have to be developed. Chapter 3 describes the development of a novel quantitative score which takes into account the amount of physiological and pharmacological support a patient is receiving. Physiological parameters were separated into those recorded regularly and those recorded intermittently. They were subsequently divided into ranges, scoring increasing points depending upon the degree of derangement. Ranges were based on an extensive literature search, currently available scores, and clinical opinion. Two key parameters viz. mean arterial pressure and oxygen saturation, were then weighted against a range of factors which can either increase or decrease their value. A score of instability could then be calculated by adding points for the weighted and unweighted parameters. After reflection using common clinical scenarios, some of the points scored in different ranges and weightings were revised to give the final quantitative score. In Chapter 4, the quantitative score was tested against data sets from actual Intensive Care patients to produce graphs of overall cardiovascular stability against time. Although this approach did capture improvements and deteriorations it had several disadvantages. It captured the expertise of a single clinician only, gave an arbitrary number which could be difficult to interpret, and the emphasis given by the clinician to the relative importance of different physiological or pharmacological parameters would not be obvious to others. Clinical reflection led to a new approach to the problem, viz. the development of the 5 point qualitative scale described in Chapter 5. Chapter 5 describes the development of a 5 point qualitative score for cardiovascular instability, underpinned by complex physiological rules, and capturing the expertise of several senior Intensive Care Clinicians. This is the Intensive Care Unit - Patient Scoring System (ICU-PSS). I scored data sets comprising thousands of predominantly hourly commonly recorded physiological and pharmacological parameters on a 5 point scale of cardiovascular stability (A to E). I also described rules in the form of different parameter ranges to indicate why I had scored time points as stable (A) through to unstable (E). These rules were incorporated into a computer programme which scored unseen data sets which I also then scored. The computer’s predicted A to E score based on these rules and my own score were compared in a confusion matrix. Mismatches with the computer prediction (based on my initial rules) were analysed and I either rescored the data if I considered that I had not assigned the correct level of instability, or modified the rule base. Through this process clinical expertise was better captured. This process was repeated with two other clinicians using my rules as a starting point. This led to further refinements of the rule base. The result was a sophisticated set of rules underpinning a 5 point, easily understandable scale of cardiovascular stability crystallising the expertise of 3 senior Intensive Care clinicians. The ICU-PSS was tested in a discrimination experiment to ascertain if clinicians could agree with the score moving in a one step and two step change. This is the first stage in full validation of the score In Chapter 6, the first stage in the validation of the ICU-PSS is described, using 10 clinicians from a city teaching and a district general hospital. It was hypothesised that if they were shown two consecutive hourly time points of physiological data from real patients and asked whether they were improving or deteriorating, they should agree with the ICU-PSS score in more than 50% of cases (random chance). In two discrimination experiments the consultants were, in random order, shown 4 examples of each type of two step improvement or deterioration in the score, e.g. A to C, and 4 examples of each type of one step change, e.g. E to D. In the two step experiment there was 92.9% agreement with the score, and in the one step change experiment, 90.9% agreement. Both were highly statistically significant. Chapter 7 describes the first of the applications of the validated score. Myocardial damage is common in Intensive Care patients and is an independent risk factor for both short and long term mortality. The mechanism in Intensive Care patients is likely to be the so-called type II damage caused by extremes of physiological derangement leading to a myocardial oxygen supply and demand imbalance. I hypothesised that it should be possible to use aspects of the score to confirm and subsequently predict where this damage is occurs based on physiological disturbance alone rather than on a rise in cardiac biomarkers. Two clinicians agreed that a subset of the level E, D and C rules from the ICU-PSS occurring in 3 out of 5 consecutive time points would represent conditions likely to lead to myocardial damage in the critically ill. Data sets with known sequences of troponin rises were scanned to ascertain if the above conditions were met around the time of a troponin rise within a sequence of troponin rises, given the natural decay of troponin. This was indeed the case in 75.8% of cases (95% CI: 57.7% to 88.9%). Similarly this set of conditions was applied to the same data sets, looking at time periods before a first troponin rise. These conditions were met in 87.5% of cases (95% CI: 61.6% to 98.1%). However, as the confidence intervals are wide (and also for the positive and negative predictive values of these tests), this early work is at best hypothesis generating. It will have to be repeated using much larger data sets. In Chapter 8, the correlation between the mean ICU-PSS score and outcome was examined. A data set of patients was prepared from Ward Watcher with an approximate 50:50 split of medical and surgical diagnoses. The physiological data from these patients was extracted from CareVue and anonymised. A mean ICU-PSS score was calculated for different points during the patient stay. The data were analysed to ascertain if there were differences in mean ICU-PSS scores at different time periods among the survivors and non-survivors within the medical and surgical groups. There is a suggestion that the mean scores are different in certain patient groups between survivors and non-survivors. However, at the time this work was undertaken the computing system used was not yet able to apply appropriate statistical tests. Future work will focus address this problem and also examine the different proportions of the patient’s stay spent in different categories of the score. This would avoid the difficulties above of converting ordinal to numerical data. In a final analysis I ascertained the relationship between degree of any troponin rise and outcome, in the population of patients at Glasgow Royal Infirmary. In a study of 100 consecutive patients, troponin rises were grouped into three categories. These were low (0.04-0.19), medium, (0.2-1.99) and high (≥2.0 micromoles/litre). Intensive Care mortailty was 13.3%, 22.7% and 40% respectively. This association is consistent with findings from similar studies elsewhere in the literature. In summary, I have developed a quantitative score of cardiovascular stability, and have developed, and partially validated, a more effective qualitative score for use in Intensive Care patients. I believe it overcomes the salient disadvantages of other currently available scores. I have demonstrated that it may be possible to confirm the presence of, and detect, where myocardial damage is occuring. Work thus far suggests that there may be an association between this score alone and outcome. Future work will focus on translating the score into a bedside monitor to give a continuous reading of the overall physiological state of the patient, to detect deterioration before it becomes clinically obvious. Characteristic patterns of deterioration associated with impending myocardial damage will be displayed at the bedside with the prospect of earlier intervention aimed at preventing myocardial damage and its associated poor outcome

A Metabolomics approach for the diagnosis Of SecondAry InfeCtions in COVID-19 (MOSAIC): a study protocol

Background: Critically ill patients with COVID-19 are at an increased risk of developing secondary bacterial infections. These are both difficult to diagnose and are associated with an increased mortality. Metabolomics may aid clinicians in diagnosing secondary bacterial infections in COVID-19 through identification and quantification of disease specific biomarkers, with the aim of identifying underlying causative microorganisms and directing antimicrobial therapy. Methods: This is a multi-centre prospective diagnostic observational study. Patients with COVID-19 will be recruited from critical care units in three Scottish hospitals. Three serial blood samples will be taken from patients, and an additional sample taken if a patient shows clinical or microbiological evidence of secondary infection. Samples will be analysed using LC–MS and subjected to bioinformatic processing and statistical analysis to explore the metabolite changes associated with bacterial infections in COVID-19 patients. Comparisons of the data sets will be made with standard microbiological and biochemical methods of diagnosing infection. Discussion: Metabolomics analyses may provide additional strategies for identifying secondary infections, which might permit faster initiation of specific tailored antimicrobial therapy to critically ill patients with COVID-19

Short- and long-term outcomes of intensive care patients with acute kidney disease

Background: Acute kidney disease (AKD) is a proposed definition for acute kidney injury (AKI) lasting 7 days or longer. Little has been reported regarding characteristics of patients with AKD and their short- and long-term outcomes. We describe the epidemiology and risk factors for AKD and outcomes following AKD. Methods: This retrospective observational cohort study identified patients aged 16 or older admitted to the Glasgow Royal Infirmary and Queen Elizabeth University Hospital intensive care units (ICUs) in Scotland between 1st July 2015 and 30th June 2018. Baseline serum creatinine and subsequent values were used to identify patients with de-novo kidney injury (DNKI). Patients with recovery prior to day 7 were classified as AKI; recovery at day 7 or beyond was classified as AKD. Outcomes were in-hospital and long-term mortality, and proportion of major adverse kidney events (MAKEs). Multivariable logistic regression was used to identify risk factors for AKD. A Cox proportional hazards model was used to identify factors associated with long-term outcomes. Findings: Of the 5,334 patients admitted to ICU who were assessed for DNKI, 1,620 (30·4%) suffered DNKI and of these, 403 (24·9%) met AKD criteria; 984 (60·7%) were male and the median age was 60·0 (IQR=48·0–72·0). Male sex, sepsis and lower baseline estimated glomerular filtration rate (eGFR) were associated with development of AKD. In-ICU (16·1%vs6·2%) and in-hospital (26·1%vs11·6%) mortality rates were significantly higher in AKD patients than AKI patients. Long-term survival was not different for AKD patients (HR=1·16; p-value=0·261) but AKD was associated with subsequent MAKEs (OR=1·25). Interpretation: One in four ICU patients with DNKI met AKD criteria. These patients had an increased risk of short-term mortality and long-term MAKEs. Whilst the trend for long-term survival was lower, this was not significantly different from shorter-term AKI patients. Patients with AKD during their ICU stay should be identified to initiate interventions to reduce risk of future MAKEs. Funding: No funding was associated with this study

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters

Measurement of isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV

Isolated photon production is measured in proton-proton and lead-lead collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80 GeV with the CMS detector at the LHC. The measured ET spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon ET-differential yields, scaled by the number of incoherent nucleon-nucleon collisions, is consistent with unity for all PbPb reaction centralities.Comment: Submitted to Physics Letters

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Observation of a new Xi(b) baryon

The first observation of a new b baryon via its strong decay into Xi(b)^- pi^+ (plus charge conjugates) is reported. The measurement uses a data sample of pp collisions at sqrt(s) = 7 TeV collected by the CMS experiment at the LHC, corresponding to an integrated luminosity of 5.3 inverse femtobarns. The known Xi(b)^- baryon is reconstructed via the decay chain Xi(b)^- to J/psi Xi^- to mu^+ mu^- Lambda^0 pi^-, with Lambda^0 to p pi^-. A peak is observed in the distribution of the difference between the mass of the Xi(b)^- pi^+ system and the sum of the masses of the Xi(b)^- and pi^+, with a significance exceeding five standard deviations. The mass difference of the peak is 14.84 +/- 0.74 (stat.) +/- 0.28 (syst.) MeV. The new state most likely corresponds to the J^P=3/2^+ companion of the Xi(b).Comment: Submitted to Physical Review Letter

Search for a W ' boson decaying to a muon and a neutrino in pp collisions at √s =7 TeV

This is the Pre-Print version of the Article. The official published version can be accessed from the link below - Copyright @ 2011 ElsevierA new heavy gauge boson, W', decaying to a muon and a neutrino, is searched for in pp collisions at a centre-of-mass of 7 TeV. The data, collected with the CMS detector at the LHC, correspond to an integrated luminosity of 36 inverse picobarns. No significant excess of events above the standard model expectation is found in the transverse mass distribution of the muon-neutrino system. Masses below 1.40 TeV are excluded at the 95% confidence level for a sequential standard-model-like W'. The W' mass lower limit increases to 1.58 TeV when the present analysis is combined with the CMS result for the electron channel.This work is supported by the FMSR (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); Academy of Sciences and NICPB (Estonia); Academy of Finland, ME, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF and WCU (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); PAEC (Pakistan); SCSR (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MST and MAE (Russia); MSTD (Serbia); MICINN and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); TUBITAK and TAEK (Turkey); STFC (United Kingdom); DOE and NSF (USA)

Measurement of the charge ratio of atmospheric muons with the CMS detector

This is the pre-print version of this Article. The official published version can be accessed from the link below - Copyright @ 2010 ElsevierWe present a measurement of the ratio of positive to negative muon fluxes from cosmic ray interactions in the atmosphere, using data collected by the CMS detector both at ground level and in the underground experimental cavern at the CERN LHC. Muons were detected in the momentum range from 5 GeV/c to 1 TeV/c. The surface flux ratio is measured to be 1.2766 \pm 0.0032(stat.) \pm 0.0032 (syst.), independent of the muon momentum, below 100 GeV/c. This is the most precise measurement to date. At higher momenta the data are consistent with an increase of the charge ratio, in agreement with cosmic ray shower models and compatible with previous measurements by deep-underground experiments

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362