Decision trees for identifying predictors of treatment effectiveness in clinical trials and its application to ovulation in a study of women with polycystic ovary syndrome.
BACKGROUND
Double-blind, randomized clinical trials are the preferred approach to demonstrating the effectiveness of one treatment against another. The comparison is, however, made on the average group effects. While patients and clinicians have always struggled to understand why patients respond differently to the same treatment, and while much hope has been held for the nascent field of predictive biomarkers (e.g. genetic markers), there is still much utility in exploring whether it is possible to estimate treatment efficacy based on demographic and baseline variables.


METHODS
The pregnancy in polycystic ovary syndrome (PPCOS) study was a prospective, multi-center, randomized clinical trial comparing three ovulation induction regimens: clomiphene citrate (CC), metformin and the combination of the two. There were 446 women who ovulated in response to the treatments among the entire 626 participants. In this report, we focus on the 418 women who received CC (alone or combined with metformin) to determine if readily available baseline physical characteristics and/or easily obtainable baseline measures could be used to distinguish treatment effectiveness in stimulating ovulation. We used a recursive partitioning technique and developed a node-splitting rule to build decision tree models that reflected within-node and within-treatment responses.


RESULTS
Overall, the combination of CC plus metformin resulted in an increased incidence of ovulation compared with CC alone. This is particularly so in women with relatively larger left ovarian volumes (≥ 19.5 cubic cm), and a left ovarian volume <19.5 cubic cm was related to treatment outcomes for all subsequent nodes. Women who were older, who had higher baseline insulin, higher waist-to-hip circumference ratio or higher sex hormone-binding globulin levels had better ovulatory rates with CC alone than with the combination of CC plus metformin.


CONCLUSIONS
Polycystic ovary syndrome (PCOS) is a phenotypically diverse condition. Both baseline laboratory and clinical parameters can predict the ovulatory response in women with PCOS undergoing ovulation induction. Without a priori hypotheses with regard to any predictors, the observation regarding left ovary volume is novel and worthy of further investigation and validation.
Zhang
Heping
H
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520-8034, USA. heping.zhang@yale.edu
Legro
Richard S
RS
Zhang
Jeffrey
J
Zhang
Leon
L
Chen
Xiang
X
Huang
Hao
H
Casson
Peter R
PR
Schlaff
William D
WD
Diamond
Michael P
MP
Krawetz
Stephen A
SA
Coutifaris
Christos
C
Brzyski
Robert G
RG
Christman
Gregory M
GM
Santoro
Nanette
N
Eisenberg
Esther
E
D000367:Age Factors; D000728:Androgens / Q000097:blood; D000858:Anovulation / Q000188:drug therapy; D015992:Body Mass Index; D002996:Clomiphene / Q000627:therapeutic use; D003663:Decision Trees; D004359:Drug Therapy, Combination; D005260:Female; D005300:Fertility Agents, Female / Q000627:therapeutic use; D006801:Humans; D007247:Infertility, Female / Q000188:drug therapy*; D008687:Metformin / Q000627:therapeutic use; D009929:Organ Size; D010062:Ovulation Induction; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy*; D011247:Pregnancy; D011384:Proinsulin / Q000097:blood; D016032:Randomized Controlled Trials as Topic; D012738:Sex Hormone-Binding Globulin / Q000032:analysis; D016896:Treatment Outcome; D049629:Waist-Hip Ratio
D000728:Androgens; D005300:Fertility Agents, Female; D012738:Sex Hormone-Binding Globulin; D002996:Clomiphene; D011384:Proinsulin; D008687:Metformin