Optimising Resource Allocation Via Prediction of Outcomes for Covid-19

Background.

Relatively simple clinical risk scores based upon easily available clinical information can
greatly aid in the triaging of patients to early discharge or more rapid and intensive
intervention. One example of this is in upper gastrointestinal bleeding where several such
scores (https://www.mdcalc.com/glasgow-blatchford-bleeding-score-gbs4 5;
https://www.mdcalc.com/rockall-score-upper-gi-bleeding-complete6) have permitted safe early
discharge thereby relieving pressure on hospitals. The investigators believe that similar
results might potentially be achievable from data routinely collected in our trust on
patients with proven or suspected Covid-19.

Objectives

The investigators aim to answer the following questions

1. What pattern of clinical history and symptoms, observations, blood and other
investigative markers best predicts that a patient suspected of Covid-19 or proven to
have it will progress to requiring ventilation?

2. What pattern of clinical history and symptoms, observations, blood and other
investigative markers best predicts that a patient suspected of Covid-19 or proven to
have it will die during their illness?

3. What pattern of clinical history and symptoms, observations, blood and other
investigative markers best predicts that a patient suspected of Covid-19 or proven to
have it will make a full recovery without requiring supplemental oxygen?

Methods

The investigators propose to two main approaches to the first two of the aims above.

A standard approach assessing baseline characteristics to predict poor outcome, similar to
other ongoing studies like ISARIC and PRIEST, but benefitting from an unbiased sample of
patients as no additional samples or data are to be collected and so the investigators
believe that it will be ethically acceptable subject to due attention to confidentiality to
analyse all patients presenting and not only those willing and able to consent.

A multi-level modelling approach that uses the rich repeated daily laboratory and clinical
measurements to predict the daily risk of a subsequent deterioration.

This second approach complements other ongoing studies like ISARIC and PRIEST, as it can only
feasibly be delivered within a single institution like NUH as it requires detailed
longitudinal linked electronic health data. Furthermore, it is an efficient, low cost study
design that does not require manual data collection.

The investigators will utilize the data held in the electronic systems of Nottingham
University Hospitals (NUH) NHS Trust, to identify all patients either suspected of having
Covid-19 infection or in whom the diagnosis is eventually confirmed. This will be performed
from the start of the pandemic retrospectively and then in a rolling program prospectively to
maximise available data.

For these patients the investigators will gather all relevant data on diagnoses
(comorbidities), daily clinical observations and daily laboratory parameters both at
presentation and on a rolling basis going forward from that until the point of death or
discharge. These data will include repeated measures of, temperature, pulse, blood oxygen
saturation, inspired oxygen concentration, respiratory rate, C reactive protein, and white
cell count among others.

Data will be analysed, and outcomes modelled within the Nottingham University Hospitals Trust
network to ensure that confidentiality is maintained.

Analysis

Characteristics of patients who go on to intubation The investigators will assess the
association of any baseline parameters and demographics of patients who require ventilation
compared to those who do not by cross tabulating baseline parameters with ventilation, and
calculating adjusted associations using a logistic regression model. The investigators will
also examine daily risk of intubation using a random effects model with the repeated daily
measurements. In order to examine the potential for an easily calculable clinical risk score,
logistic models will be prepared, but retaining continuous variables as continuous (to
maximise the retention of useful predictive data) and reducing them to categorical data (for
ease of clinical calculation). The investigators will select predictors for the model using
backward elimination with the Akaike information criterion and alpha = 0.05. For candidate
models the investigators will calculate the C-index and receiver operating curves and assess
calibration using the Hosmer-Lemeshow test. Bootstrapping and cross validation will be used
to avoid overfitting and assess model performance.

Time trends analysis to identify markers leading to intubation The investigators will examine
the data for trends over time in repeated measurements where available and describe these
using appropriate summary statistics. If there are enough repeated measurements, then each
covariate will be assessed with a JoinPoint analysis to assess if there is an obvious
inflexion in time to indicate a change in the clinical picture which marks a decline towards
ventilation. This process will feed into the rational choice of categories for categorical
representation of the data.

Predictors at intubation suggesting death The investigators will assess the association of
any parameters and demographics of ventilated patients who die compared to those who do not
by cross tabulating parameters at point of ventilation with death, and calculating adjusted
associations using a logistic regression model. The investigators will also examine daily
risk of death using a random effects model with the repeated daily measurements. In order to
examine the potential for an easily calculable clinical risk score, logistic models will be
prepared, but retaining continuous variables as continuous (to maximise the retention of
useful predictive data) and reducing them to categorical data (for ease of clinical
calculation). The investigators will select predictors for the model using backward
elimination with the Akaike information criterion and alpha = 0.05. For candidate models the
investigators will calculate the c index and receiver operating curves and assess calibration
using the Hosmer-Lemeshow test. Bootstrapping and cross validation will be used to avoid
overfitting and assess model performance.

Time trends analysis to identify markers leading to death We will examine the data for trends
over time in repeated measurements where available and describe these using appropriate
summary statistics. If there are enough repeated measurements, then each covariate will be
assessed with a JoinPoint analysis to assess if there is an obvious inflexion in time to
indicate a change in the clinical picture which marks a decline towards death Baseline
characteristics of patients discharged without supplemental oxygen We will assess the
association of any baseline parameters and demographics of patients who are discharged
without supplemental oxygen compared to those who are not by cross tabulating baseline
parameters with ventilation, and calculating adjusted associations using a logistic
regression model. In order to examine the potential for an easily calculable clinical risk
score, logistic models will be prepared, but retaining continuous variables as continuous (to
maximise the retention of useful predictive data) and reducing them to categorical data (for
ease of clinical calculation). The investigators will select predictors for the model using
backward elimination with the Akaike information criterion and alpha = 0.05. For candidate
models the investigators will calculate the c index and receiver operating curves and assess
calibration using the Hosmer-Lemeshow test. Each of these steps will be repeated in 10
randomly selected 20% subsamples of the dataset.

Stratified supplemental analyses To identify different patient groups at risk of poor
outcomes, interactions with each risk model will be assessed to identify if stratification is
needed by age bands, sex, prior co-morbidities and baseline factors such as lymphopaenia, CRP
etc.

All analyses will be repeated for groups of PCR proven Covid-19 patients and those only
suspected.

For the analysis of discharge without supplemental oxygen the investigators will examine the
risk of readmission for those so discharged and repeat the analysis only for those not
subsequently readmitted.

Eligibility Criteria

Inclusion criteria • All patients admitted to Nottingham University Hospitals Trust either
suspected of having Covid-19 infection or in whom the diagnosis is eventually confirmed and
who are over the age of 18 years

Exclusion criteria

• Aged under 18.