https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(00)02039-0.pdf

Subgroup analysis and other (mis)uses of baseline data in clinical trials.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1939-4640.2002.tb02599.x

Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques.

Clinical trial investigators often record a great deal of baseline data on each patient at randomization When reporting the trial's findings such baseline data can be used for (i) subgroup analyses which explore whether there is evidence that the treatment difference depends on certain patient characteristics, (ii) covariate-adjusted analyses which aim to refine the analysis of the overall treatment difference by taking account of the fact that some baseline characteristics are related to outcome and may be unbalanced between treatment groups, and (iii) baseline comparisons which compare the baseline characteristics of patients in each treatment group for any possible (unlucky) differences This paper examines how these issues are currently tackled in the medical journals, based on a recent survey of 50 trial reports in four major journals The statistical ramifications are explored, major problems are highlighted and recommendations for future practice are proposed Key issues include: the overuse and overinterpretation of subgroup analyses; the underuse of appropriate statistical tests for interaction; inconsistencies in the use of covariate-adjustment; the lack of clear guidelines on covariate selection; the overuse of baseline comparisons in some studies; the misuses of significance tests for baseline comparability, and the need for trials to have a predefined statistical analysis plan for all these uses of baseline data

Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems.

Sperm DNA integrity is essential for the accurate transmission of genetic information. It has a highly compact and complex structure and is capable of decondensation-features that must be present in order for a spermatozoon to be considered fertile. Any form of sperm chromatin abnormalities or DNA damage may result in male infertility. In support of this conclusion, it was reported that in-vivo fecundity decreases progressively when > 30% of the spermatozoa are identified as having DNA damage. Several methods are used to assess sperm chromatin/DNA, which is considered an independent measure of sperm quality that may yield better diagnostic and prognostic approaches than standard sperm parameters (concentration, motility and morphology). The clinical significance of this assessment lies in its association not only with natural conception rates, but also with assisted reproduction success rates. Also, it has a serious impact on the offspring and is highly prognostic in the assessment of fertility in cancer patients. Therefore, screening for sperm DNA damage may provide useful information in cases of male idiopathic infertility and in those men pursuing assisted reproduction. Treatment should include methods for prevention of sperm DNA damage.

/pdf/role-of-sperm-chromatin-abnormalities-and-dna-damage-in-male-5a2riixlg7.pdf

Role of sperm chromatin abnormalities and DNA damage in male infertility

Recent advances in understanding of male infertility have implicated two major causative factors, oxidative stress and Y chromosome deletions. A major cause of oxidative stress appears to be the high rate of reactive oxygen species generation associated with the retention of excess residual cytoplasm in the sperm midpiece. Other possible causes include the redox cycling of xenobiotics, and antioxidant depletion or apoptosis. Oxidative stress induces peroxidative damage in the sperm plasma membrane and DNA damage in both the mitochondrial and nuclear genomes. Nuclear DNA damage in the germ line of the father may be associated with pathology in the offspring, including childhood cancer and infertility. Gene deletions on the non-recombining region of the Y chromosome account for the infertility observed in about 15% of patients with azoospermia and 5-10% of subjects with severe oligozoospermia. The Y chromosome is particularly susceptible to gene deletions because of the inability of the haploid genome to deploy recombination repair in retrieving lost genetic information. Aberrant recombination, defective chromatin packaging, abortive apoptosis and oxidative stress may all be involved in the aetiology of DNA damage in the germ line. The factors responsible for Y chromosome deletions in spermatozoa remain unresolved but may be one facet of a central reproductive problem: controlling the amount of oxidative stress experienced by germ cells during their differentiation and maturation in the male reproductive tract.

/pdf/oxidative-stress-dna-damage-and-the-y-chromosome-3dr9oq8vcx.pdf

Oxidative stress, DNA damage and the Y chromosome.

Background. The objective of this study was to determine the incidence of spermatozoa with DNA strand breaks in four clinically different groups of infertile couples, and to correlate DNA damage with other semen analysis parameters, as well as fertilization rates and IVF outcome. Methods. One group consisted of 75 men where the female partners had a tubal obstruction, Group A . Fifty sperm samples were collected from men in unexplained infertile couples, Group B . Fifty men with oligozoospermia and IVF made up Group C . Finally, 61 men with oligozoospermia and where ICSI was performed made up Group D . Sperm samples were assessed according to the WHO manual and for the presence of DNA strand breaks in spermatozoa. The study was blinded for the technician involved in the assessment of DNA strand breaks. IVF was carried out according to a long down regulation protocol using GnRH, FSH and hCG. Embryos were transferred on day 2 after fertilization with a maximum of three embryos. Results. This study demonstra...

The role of DNA strand breaks in human spermatozoa used for IVF and ICSI.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(97)02449-5.pdf

Randomised study of risk of fetal loss related to early amniocentesis versus chorionic villus sampling

Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling.

Apoptosis in human cumulus cells in relation to zona pellucida thickness variation, maturation stage, and cleavage of the corresponding oocyte after intracytoplasmic sperm injection.

Background. The purpose of this study was to examine the correlation between DNA strand breaks in human spermatozoa and semen quality, fertilization rate and IVF outcome. Methods. A total of 50 men suffering from unexplained infertility and 50 men with oligozoospermia undergoing IVF treatment entered a prospective study. Sperm samples were assessed according to the WHO manual and for the presence of DNA strand breaks in spermatozoa. The study was blinded for the technician involved in assessment of DNA strand breaks. IVF was carried out according to a long down regulation protocol using GnRH, FSH and hCG. The ova were inseminated with 200,000 spermatozoa/ml. Embryos were transferred on day 2 after fertilization with a maximum of three embryos. Results. This study demonstrates a negative correlation between the proportion of spermatozoa having DNA strand breaks and the proportion of oocytes fertilized after IVF. Conclusion. The number of human spermatozoa with DNA strand breaks is a good predictor for fert...

https://obgyn.onlinelibrary.wiley.com/doi/pdf/10.1034/j.1600-0412.2000.079003189.x

Steen Smidt-Jensen

Papers

The role of DNA strand breaks in human spermatozoa used for IVF and ICSI.

Randomised study of risk of fetal loss related to early amniocentesis versus chorionic villus sampling

Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling.

Apoptosis in human cumulus cells in relation to zona pellucida thickness variation, maturation stage, and cleavage of the corresponding oocyte after intracytoplasmic sperm injection.

DNA strand breaks in human spermatozoa: Correlation with fertilization in vitro in oligozoospermic men and in men with unexplained infertility