/******************************************************************************
* TABLE     : t_ada_impact_pk  (Single-/Fixed-Sequence, e.g. DDI)
* TITLE     : Impact of Anti-Drug Antibody (ADA) Status on Plasma PK Exposure
*             by Period
* POPULATION: PK Population (PKFL='Y') with ADA result (ADA-evaluable)
* INPUT     : ADPP (PARAMCD = CMAX, AUCLST, AUCIFO, ...) merged with per-PERIOD
*             ADA status from ADIS (matched on USUBJID and APERIOD)
* NOTE      : PSEUDOCODE. Single-/fixed-sequence (no randomized sequence):
*             column = fixed PERIOD (APERIOD/APERIODC; Period 1 = reference,
*             subsequent period(s) = test); within each period, exposure PK
*             parameters summarized by ADA status (ADA-positive vs
*             ADA-negative). PK stats = arithmetic n, Mean, SD, CV%, Geo Mean,
*             Geo CV%, Median, Min, Max. Tmax (if shown) = Median (Min, Max)
*             only. Comparison is DESCRIPTIVE (subgroup exposure by ADA status),
*             not an inferential test.
******************************************************************************/
%include "../00_setup_macros.sas";
%setup(study=CP-101, adam=/data/adam, out=/data/tfl);
%designvars(design=SINGLESEQ);     /* column = APERIODC (fixed period)       */

/*--- per-PERIOD ADA status from ADIS (carry APERIOD) --------------------*
* ADA status is matched PER PERIOD (a participant may be ADA-positive in the test
* period but negative in the reference period). Carrying APERIOD here prevents
* a single participant-level label from contaminating both period columns.       */
proc sql;
  create table _adastat as
    select USUBJID, APERIOD,
           /* ADaM-provided overall ADA status flag mapped to label:
              'ADA-positive' / 'ADA-negative' (treatment-emergent basis)     */
           max(case when ADAEMFL='Y' then 1 else 0 end) as adaemn
    from adam.adis where ADAFL='Y'
    group by USUBJID, APERIOD;
quit;

/*--- PK parameters + ADA group; keep exposure params for this table ------
* APERIOD/APERIODC retained from ADPP so exposure is read out per fixed period;
* ADA status joined on USUBJID AND APERIOD (per-period match).               */
proc sql;
  create table pp as
    select p.*,
           case when a.adaemn=1 then 'ADA-positive'
                when a.adaemn=0 then 'ADA-negative'
                else 'ADA status unknown' end as ADAGRP length=20
    from adam.adpp(where=(PKFL='Y'
                          and PARAMCD in ('CMAX','AUCLST','AUCIFO','TMAX'))) p
    left join _adastat a
      on p.USUBJID=a.USUBJID and p.APERIOD=a.APERIOD;
quit;
data pp; set pp;
  tmaxfl = (PARAMCD='TMAX');                   /* Tmax -> median (min,max)     */
  if AVAL>0 then logv = log(AVAL);             /* log value for geometric stats */
run;

/*--- arithmetic + geometric summary by period x ADA group x parameter ----
* Reuse %pkstats pattern: arithmetic n/Mean/SD/CV% + geometric on log scale */
proc means data=pp(where=(tmaxfl=0)) noprint;
  class &BYPERIOD ADAGRP PARAMCD PARAM;
  var AVAL;
  output out=_arith n=n mean=mean std=std min=min max=max cv=cv;
run;
/* geometric: PROC MEANS on log(AVAL), AVAL>0; GeoMean=exp(mean_log),
   GeoCV%=100*sqrt(exp(var_log)-1)                                           */
proc means data=pp(where=(tmaxfl=0 and AVAL>0)) noprint;
  class &BYPERIOD ADAGRP PARAMCD; var logv;                 /* log(AVAL)       */
  output out=_geo mean=gmean_log std=gsd_log;              /* on logVAL       */
run;
data _cont; merge _arith _geo; by APERIOD ADAGRP PARAMCD;
  length stat $14 value $30;
  /* round to ADaM decimal hints; build display rows:
     n / Mean / SD / CV% / Geo Mean / Geo CV% / Median / Min / Max           */
run;

/*--- Tmax: Median (Min, Max) only ---------------------------------------*/
proc means data=pp(where=(tmaxfl=1)) noprint;
  class &BYPERIOD ADAGRP PARAMCD; var AVAL;
  output out=_tmax median=med min=min max=max;
run;
data _tmaxd; set _tmax; length stat $14 value $30;
  stat='Median (Min, Max)';
  value=catx(' ', put(med,8.2), cats('(',put(min,8.2),', ',put(max,8.2),')'));
run;

/*--- stack params (rows) x [period x ADA group] (cols) ------------------*/
data _all; set _cont _tmaxd; run;
proc sort data=_all; by PARAM PARAMCD stat APERIOD ADAGRP; run;
proc transpose data=_all out=_wide;
  by PARAM PARAMCD stat;
  id APERIOD ADAGRP;                           /* period x ADA-status columns  */
  var value;
run;

%tfltitle(num=14.5.2.1, type=Table,
   text=%str(Impact of Anti-Drug Antibody (ADA) Status on Plasma PK Exposure by Period),
   pop=Pharmacokinetic Population with ADA Result,
   foot=%str(Exposure parameters summarized by ADA status (positive/negative) within each fixed period (APERIODC; Period 1 = reference, subsequent period(s) = test). CV% arithmetic; Geo CV% = 100*sqrt(exp(s^2_log)-1). Tmax: Median (Min, Max). Descriptive subgroup comparison; single-/fixed-sequence.));
proc report data=_wide nowd split='|';
  columns PARAM PARAMCD stat ("By Period and ADA Status" /* period x ADA cols */);
  define PARAM   / order 'Parameter (units)' width=26;
  define PARAMCD / order noprint;
  define stat    / display 'Statistic' width=16;
run;