An Overview of Ross Prentice’s Contributions to Statistical Science

Ross Prentice’s work has had the most profound impact on the theory and practice of statistics. His research interests range from survival analysis, longitudinal data analysis, epidemiologic designs and analysis, to genomic studies. His contributions are so broad and so deep that it would be impossible to provide a comprehensive review in any limited amount of space. In this commentary, I will attempt to give a brief tour of some of his statistical work, focusing on ten of my favorite papers of his. I will describe the main ideas in those papers and their influence on the directions of statistical research and on the designs and analysis of medical studies. I will mention a few stories along the way.     

Precision Medicine:What Challenges Are We Facing?

正Following the publication of the US National Research Council(NRC)report‘‘Toward Precision Medicine:Building a Knowledge Network for Biomedical Research and a New Taxonomy of Diseasesin 2011[1],several nations have announced that their national research programs would definitely head toward this direction.Now,precision medicine(PM)became a banner for many large-scale biomedica     

How Many Nucleotides Are Required to Resolve a Phylogenetic Problem? The Use of a New Statistical Method Applicable to Available Sequences

The evolution of bootstrap proportions (BP) with sequence length was studied using a 28S ribosomal RNA data set. For different sequence lengths, informative sites were jackknifed several times. Bootstrapping was subsequently performed on each of these subsamples. For each node, BPs so obtained were plotted against sequence length, showing the evolution of the robustness with increasing number of informative sites. For robust nodes (BP of 100%), the pattern of BPs is unvarying and is described by a simple function BP = 100(1− e^{−b(x − x′)}), where x is the number of informative sites and b and x′ are two parameters estimated using a nonlinear regression procedure. When a node has a BP <100% and the pattern of BPs fits this function, it is possible to estimate the number of informative sites required to obtain a given average BP. The method also identifies nonrobust nodes (nonascending clusters of BP dots), for which it seems to be more cost effective and fruitful to turn to other species and/or genes rather than to continue sequencing longer gene lengths from the same species to reach a BP of 95%.     

Are mouse telomeres going to pot?

Pot1 is a conserved single-stranded DNA binding protein with crucial functions in the protection of telomeres and maintenance of their length. In this issue of Cell, two papers (Hockemeyer et al., 2006; Wu et al., 2006) examine the roles of murine Pot1 homologs and describe intriguing new insights into how cells protect their chromosome ends from DNA-repair activities.     

Are aromatase inhibitors superior to antiestrogens?

Aromatase inhibitors (AIs) have been in use to treat metastatic breast cancer for over 25 years. Recently potent and specific AIs have been introduced, which, because of their low toxicity profile, are being used in the adjuvant and neoadjuvant situation and also for the prevention of breast cancer. The two non-steroidal AIs, anastrozole and letrozole, and the steroidal AI, exemestane, have all shown superiority to tamoxifen as first-line treatment for advanced breast cancer. Interestingly, the oestrogen receptor downregulator, fulvestrant, was shown to be equivalent to anastrozole when compared as second-line therapy after the failure of tamoxifen. The first adjuvant AI trial began in 1996 and recruited over 9000 patients (ATAC trial). Anastrozole was compared with tamoxifen and a combination of the two drugs. There were no significant differences between tamoxifen and the combination. However, anastrozole showed about a 20% improvement in disease-free survival in ER+ disease compared with the other treatments. An overall survival analysis will be reported later this year. Two trials have compared 5 years of tamoxifen with 2–3 years of tamoxifen, followed by 2–3 years of AI (one trial (ITA) used anastrozole and another (intergroup) exemestane). Both trials show a disease-free advantage for the switch to AI. In another study (MA17) 5 years of tamoxifen was followed by a randomisation to letrozole or placebo and showed a significant disease-free advantage to the AI. Both letrozole and anastrozole show superiority to tamoxifen when used as a neoadjuvant therapy. Anastrozole significantly reduced contralateral breast cancer compared with tamoxifen, and this has led to two prevention trials: one in women at risk comparing anastrozole with placebo and the other after excision of DCIS comparing anastrozole with tamoxifen (IBIS II). The NCI Canada has also just initiated a trial of exemestane for prevention. Nearly all data available indicate that AIs are superior to tamoxifen. The important question is whether survival is improved when they are used as adjuvant therapy?     

Transgenerational Epigenetic Contributions to Stress Responses: Fact or Fiction?

There has been increasing interest in the possibility that behavioral experience—in particular, exposure to stress—can be passed on to subsequent generations through heritable epigenetic modifications. The possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. Nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability. This Perspective provides an overview of the multiple meanings of the term epigenetic, discusses the challenges of studying epigenetic contributions to stress susceptibility—and the experimental evidence for and against the existence of such mechanisms—and outlines steps required for future investigations.     

Are ubiquitination pathways central to Parkinson's disease?

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. The major motor disabilities of PD are associated with the extensive loss of dopaminergic neurons in the substantia nigra pars compacta. The physiological changes and biochemical pathways involved in the selective demise of these neurons are still unclear. Recent studies have demonstrated that alterations or reductions in ubiquitin-mediated proteasome function can be causal of at least some forms of parkinsonism, and multiple lines of evidence suggest that this mechanism of protein degradation may play an important role in the etiology of PD.     

Are Unfamiliar Neighbours Considered to Be Dear-Enemies?

Background

Discriminating threatening individuals from non-threatening ones allow territory owners to modulate their territorial responses according to the threat posed by each intruder. This ability reduces costs associated with territorial defence. Reduced aggression towards familiar adjacent neighbours, termed the dear-enemy effect, has been shown in numerous species. An important question that has never been investigated is whether territory owners perceive distant neighbours established in the same group as strangers because of their unfamiliarity, or as dear-enemies because of their group membership.

Methodology/Principal Findings

To investigate this question, we played back to male skylarks (Alauda arvensis) songs of adjacent neighbours, distant neighbours established a few territories away in the same microdialect area and strangers. Additionally, we carried out a propagation experiment to investigate how far skylark songs are propagated in their natural habitat and we estimated repertoire similarity between adjacent neighbours, distant neighbours and strangers. We show that skylarks, in the field, respond less aggressively to songs of their distant and likely unfamiliar neighbours, as shown by the propagation experiment, compared to stranger songs. The song analysis revealed that individuals share a high amount of syllables and sequences with both their adjacent and distant neighbours, but only few syllables and no sequences with strangers.

Conclusions

The observed reduction of aggression between distant neighbours thus probably results from their familiarity with the vocal group signature shared by all members of the neighbourhood. Therefore, in skylarks, dear-enemy-like relationships can be established between unfamiliar individuals who share a common acoustic code.     

Are Biomphalaria snails resistant to Schistosoma mansoni?

Among Biomphalaria glabrata/Schistosoma mansoni snail-trematode combinations, it appears that some parasites succeed whilst others fail to infect snails. Snails that become infected are termed susceptible hosts. Those which are not infected are traditionally determined as 'resistant'. Here the concept of B. glabrata resistance to S. mansoni is re-examined in the light of additional observations. It is suggested that, in B. glabrata/S. mansoni, compatibility is tested independently for each individual miracidium and host, and that the success or failure of an infection does not depend on the snail susceptibility/resistance status, but on the 'matched' or 'mismatched' status of the host and parasite phenotypes.     

MITOCHONDRIA: Are mitochondria accessory to metastasis?

Since the nineteenth century the importance of mitochondria in cellular physiology has been growing steadily. Not only the organelle harbors the main systems for ATP generation, but also buffers the redox potential in the cytosol and is one of the protagonists of the intrinsic pathway for apoptosis. In tumor cells, mitochondria went from being dysfunctional compartments to playing a supportive or perhaps even a triggering part in metastasis. This “Organelle In Focus” article discusses the classical metabolic events that occur in mitochondria and why these pathways could be essential for the onset of the malignant phenotype. Finally, we propose that the oxidative metabolism of tumor cells in conjunction with the inactivation of anoikis may have been coopted through a non-adaptive evolutionary process.