Chapter 10 Multi-event variables

10.1 Date and time variables

As dates and times are used across events to capture delays between an event and another (e.g. between index cardiotoxicity and death), there are attributed a specific naming scheme:

  • They do not start by the event identifier

  • They have their own identifier date for dates and ti for times.

  • Time variables always have 3 components:

    • The ti identifier

    • The first event identifier

    • The second event identifier

There is an exception to this naming rule: time between 2 cures of ICI (either previous line or current line), which has the long suffix regimen_freq.

For example, time between index cardiotoxicity and death is ti_ic_death. An event identifier can have a middle _ if its very long (e.g. cl1stctla4_other for current line first dose of an unspecified anti-CTLA4, although this is quite a rare case.

Time variables represent delays between two dates.

Of note, times can be expressed in days, weeks or years.

var event unit quick desc
ti_tobaccoquit_ic demo years From tobacco quitting to IC
ti_otx_ic demo years From organ transplant x to IC
ti_plicistop_ic demo days From previous line ICI stop (end of regimen) to IC
pl_drug_regimen_freq previous_line weeks From one cure to another, during an ICI therapy regimen
ti_ic_1ststeroid ic days From IC to first dose of steroids
ti_cl1stnivo_ic cl days From current line ICI-drug 1st infusion to IC
ti_ic_ihdischarge ih days Length of hospital stay

10.2 Time to cardiotoxicity onset from immune checkpoint inhibitor introduction

As the title suggests, the idea is to collect the time to onset between the first dose of immune checkpoint inhibitor received during the current cycle and the occurrence of cardiotoxicity.

This data is stored at the immune checkpoint inhibitor level, e.g., a patient who received nivolumab will have this data stored in a nivolumab specific variable. The structure for this data is

Current Target Description
start_days_drug ti_icistart_ic_drug

It is a delay, in days. Drug name is abbreviated here in the current naming (e.g. nivo for nivolumab). Sometimes, the drug name is wrong (see below)

Could be : time variable (ti_) from (ici_start) to index cardiotoxicity (ic), for drug (drug complete name)
start_days_drugx ti_icistart_ic_drug__calc

Same but computed from dates (when available). Mind the “x” at the end of the name

Could be: same but with a standardized suffix indicating a calculation
first_doses_drug_mce Drug name is complete here. It is an old variable which has now the \@ HIDDEN status, and is similar to start_days_drugx

To capture this time to onset, you have to check every possibilities for a patient, e.g. you must check for all immune checkpoint inhibitor level time variables and choose which of these 3 variables you keep first, if ever more than one is available. This gives a quite heavy piece of code

ti_icistart_ic = expr(pmax( # pmax here: maximum delay (in the case multiple ICI were prescribed sequentially)
   eval(tto_uni_3v(start_days_nivo,
                 start_days_nivox,
                 first_doses_nivolumab_mce)), # identical to start_days_nivox but it is @HIDDEN
   eval(tto_uni_3v(start_days_pem,
                 start_days_pemx,
                 first_doses_pembrolizumab_mce)), # @HIDDEN
   eval(tto_uni_3v(start_days_pem_2, # Other Anti-PD1 regimen
                 start_days_pem_2x,
                 first_doses_pembrolizumab_mce_2)),# @HIDDEN
   eval(tto_uni_3v(start_days_pem_3, # Cemiplimab 
                 start_days_pem_3x,
                 first_doses_pembrolizumab_mce_3)),
   eval(tto_uni_3v(start_days_atez,
                 start_days_atezx,
                 first_doses_atezolizumab_mce)),
   eval(tto_uni_3v(start_days_ave,
                 start_days_avex,
                 first_doses_avelumab_mce)),
   eval(tto_uni_3v(start_days_durv,
                 start_days_durvx,
                 first_doses_durvalumab_mce)),
   eval(tto_uni_3v(start_days_durv_3,# Ohter Anti-PDL1
                 start_days_durv_3x,
                 first_doses_durvalumab_mce_3)),
   eval(tto_uni_3v(start_days_ipi,
                 start_days_ipix,
                 first_doses_ipilimumab_mce)),
   eval(tto_uni_3v(start_days_trem,
                 start_days_tremx,
                 first_doses_tremelimumab_mce)),
   eval(tto_uni_3v(start_days_trem_2, # Other Anti-CTLA4
                 start_days_trem_2x,
                 first_doses_tremelimumab_mce_2)),
    na.rm = TRUE
  ) - # look at the minus!! Shall we keep it? 2022-09-16
    eval(numvar_uni(cardiotox_days_1,
                    cardiotox_days_1x))
    # Number of days before presentation that Myocarditis symptoms began
     
  )

Where eval(tto_univ_3v()) would be a prioritizer function among the 3 variables. Note that we might want to substract the cardiotox_days_1 delay, if we’re interested in the beginning of symptoms rather than index date of referral.

10.3 Death

  • ih_ou_death : During index hospitalization

  • fu_death : During follow-up (later than discharge)

10.4 Electrocardiograms

  • be : Baseline (before immune checkpoint inhibitor current cycle 1st infusion)

  • be2 : The same +++ it is a duplicate in a separate event (should be merged in the future). There are more features here.

  • ie : Index cardiotoxicity (1st EKG at the time of cardiotoxicity diagnosis)

  • ie2 : The same ++ it is a duplicate in a separate event (should be merged in the future). There are more features here.

  • ih_ekg : Additional EKG(s) during index hospitalization

  • fu_ekg : Most recent EKG during follow-up

10.4.1 Features

Variable Definition
exist Availability of said EKG
analysis All EKG diagnoses (rhythm, durations, repolarization…)

cornell_voltage

sokolow_lyon_voltage

heart_rate

pr_duration

qrs_duration

qt_duration (also qtcb, qtcf)

 Numeric features (only available for be2 and ie2)

Also, timings according to index cardiotoxicity, and upload variables.