This paper describes the implementation of a flexible method in R for fitting a regression model to possibly non-Markov progressive illness-death data. The idmTPreg package offers the user the opportunity to estimate possibly time-varying effect of covariates on the transition probabilities for the progressive illness-death model. We have explained the use of the idmTPreg package by applying the method to a colon cancer dataset. The results in this paper were obtained using R 3.4.2. In a future version of the package, we plan to implement a similar method to estimate coefficients on net survivals for a progressive illness-death in a relative survival setting ; This work was supported by funding from the European Community's Seventh Framework Programme FP7/2011: Marie Curie Initial Training Network MEDIASRES ("Novel Statistical Methodology for Diagnostic/Prognostic and Therapeutic Studies and Systematic Reviews"; www.mediasres-itn.eu) with the Grant Agreement Number 290025, by the Basque Government through the BERC 2014-2017 program, by Spanish Ministry of Economy and Competitiveness MINECO: BCAM Severo Ochoa excellence accreditation SEV-2013-0323, Grant MTM2016-76969-P and European Regional Development Fund (ERDF). The second author acknowledges financial support from Ministerio de Economía y Competitividad Grant MTM2016-76969-P and European Regional Development Fund (ERDF) ; SI
In: Schrijver , L H , Antoniou , A C , Olsson , H , Mooij , T M , Roos-Blom , M-J , Azarang , L , Adlard , J , Ahmed , M , Barrowdale , D , Davidson , R , Donaldson , A , Eeles , R , Evans , D G , Frost , D , Henderson , A , Izatt , L , Ong , K-R , Bonadona , V , Coupier , I , Faivre , L , Fricker , J-P , Gesta , P , van Engelen , K , Jager , A , Menko , F H , Mourits , M J E , Singer , C F , Tan , Y Y , Foretova , L , Navratilova , M , Schmutzler , R K , Ellberg , C , Gerdes , A-M , Caldes , T , Simard , J , Olah , E , Jakubowska , A , Rantala , J , Osorio , A , Hopper , J L , Phillips , K-A , Milne , R L , Terry , M B , Nogues , C , Engel , C , Kast , K , Goldgar , D E , van Leeuwen , F E , Easton , D F , Andrieu , N & Rookus , M A 2021 , ' Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers : an international cohort study ' , American Journal of Obstetrics and Gynecology , vol. 225 , no. 1 , pp. 51.e1-51.e17 . https://doi.org/10.1016/j.ajog.2021.01.014 ; ISSN:0002-9378
Background Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. Objective This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. Study Design In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent–weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. Results Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more ...
In: Schrijver, Lieske H., Antoniou, Antonis C., Olsson, Hakan orcid:0000-0002-8794-9635 , Mooij, Thea M., Roos-Blom, Marie-Jose, Azarang, Leyla, Adlard, Julian, Ahmed, Munaza, Barrowdale, Daniel, Davidson, Rosemarie, Donaldson, Alan, Eeles, Ros, Evans, D. Gareth, Frost, Debra, Henderson, Alex, Izatt, Louise, Ong, Kai-Ren, Bonadona, Valerie, Coupier, Isabelle, Faivre, Laurence, Fricker, Jean-Pierre, Gesta, Paul, van Engelen, Klaartje, Jager, Agnes, Menko, Fred H., Mourits, Marian J. E., Singer, Christian F., Tan, Yen Y., Foretova, Lenka orcid:0000-0003-0494-2620 , Navratilova, Marie, Schmutzler, Rita K., Ellberg, Carolina, Gerdes, Anne-Marie, Caldes, Trinidad, Simard, Jacques orcid:0000-0001-6906-3390 , Olah, Edith, Jakubowska, Anna, Rantala, Johanna, Osorio, Ana orcid:0000-0001-8124-3984 , Hopper, John L., Phillips, Kelly-Anne, Milne, Roger L., Terry, Mary Beth, Nogues, Catherine, Engel, Christoph orcid:0000-0002-7247-282X , Kast, Karin, Goldgar, David E., van Leeuwen, Flora E., Easton, Douglas F., Andrieu, Nadine and Rookus, Matti A. (2021). Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study. Am. J. Obstet. Gynecol., 225 (1). NEW YORK: MOSBY-ELSEVIER. ISSN 1097-6868
Obstetrical complications, often referred to as the great obstetrical syndromes, are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and cli-nicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes.