Soil genesis and classification in the Whiteoak Mountain fault block in East Tennessee

Geological processes have forged an atypical region of geomorphic and stratigraphic diversity in the Ridge and Valley physiographic region of East Tennessee. Soils developing in the melange of parent materials reflect this heterogeneity. Objectives of this study were 1) to better understand the geological stratigraphy of the Ridge and Valley area, 2) to determine the genesis of soils forming in a variety of parent materials, 3) to examine soils forming in specific parent materials to discern properties uniquely characteristic to those soils, 4) to identify specific properties utilizable for field recognition of these soils, and 5) to classify these soils to the family level. Within the Whiteoak Mountain fault block, geologies range from the Cambrian Rome Formation to the Ordovician Moccasin Formation. Properties of each rock unit vary to some extent. This complexity has induced a great diversity in soil genesis. Sixty-one pedons from the Whiteoak Mountain thrust block were sampled for soil genesis and classification. A transect of thirteen soils was examined over a sequence of Cambrian to Ordovician aged geological units including the Rome Formation, Knox Group, and the Chickamauga Group. Soil genesis of forty-eight pedons directly related to the Copper Ridge Formation and the Maryville Formations were studied in Roane and Anderson Counties, Tennessee. Soil morphology was described for each site. Horizonization, texture, structure, consistency, redoximorphic features, and any other observable property was noted during excavation. Laboratory analyses for soil characterization included pH, total carbon, particle size, free iron oxides, cation exchange capacity, percent base saturation, total acidity, KCl extractable aluminum, and hydroxylamine-HCl extractable manganese. Parent materials in the thirteen soil transect included alluvium, colluvium, and residuum. Soils evolved from Chickamauga Group geologies were classified as Typic Paleudults and Typic Hapludalfs. Classification of soils developing in materials from members of the Knox Group IV included Typic Paleudults, Typic Fragiudults, Typic Kandiudults, Typic Hapludalfs and Typic Hapludults. The Rome Formation had weathered to form soils classified as Ultic Hapludalfs and Typic Hapludults. Soils derived from fault breccia and an alluvial/colluvial deposition were classified as a Typic Hapludalf and Typic Hapludult, respectively. The primary differences among these pedons resulted from the influences of geological parent material, site position, slope, and erosion. Soil formation in Copper Ridge parent materials resulted in development of low activity clays with kandic horizonization. Of the 24 pedons examined, 54% had developed kandic horizons. Kandic horizons with hues of 5YR and 2.5YR had average clay contents of 49 and 68%, respectively. Non-kandic argillic horizons averaged 34 and 55% clay in the 5YR and 2.5YR horizons. Kandic horizons had developed in both colluvial and residual materials. For field identification, intense redness of soil matrix color along with high clay content in soils forming in Copper Ridge colluvium/residuum would present a greater than 54% possibility that kandic horizonization had occurred. Soil evolution in Maryville parent materials was very consistent over the twenty-four pedons examined. These soils were not very deeply weathered. Paralithic contact occurred at less than 100 cm in 75% of the pedons. Particle size class was predominantly clayey. Classification varied primarily due to thickness of the argillic horizon. Forty-two percent were Ochreptlc Hapludults, while the remaining 58% were Typic Hapludults. Weathering of the diversity of rock units in the Ridge and Valley physiographic region has resulted formation of a variety of soils. Soils properties were directly related to the geological parent material with variations primarily resulting from differences in site position. Knowledge of the geological lithologies of a region is a valuable tool in the examination of soil genesis and classification

Spatial variability of soil solution nitrates and soil morphology as effected by long term management on a Highland Rim site

A study of the effects of long term management and soil morphology on distribution of soil solution nitrates and chlorides was conducted at the Highland Rim Experiment Station in Robertson County, Tennessee. The site area was a soil fertilization study which had been under continuous corn for 28 years. Two sites were fertilized annually with 336 kg ha-1 nitrogen, 112 kg ha-1 phosphorus, 336 kg ha-1 potassium, and 56 kg ha-1 of a minor element supplement. Two other sites received this same treatment plus 10 tons/acres of manure. Two control sites were sampled in undisturbed native soils on the same landscape. Six pedons were sampled to study spatial variability of the soil taxon. The effect of manuring and long term management on measured soil chemical properties was determined. Fourteen points in each of two plots were randomly sampled to determine distribution and quantity of soil solution nitrates and chlorides. Field morphology included horizon designations, depth, boundary distinctness, texture, color, consistence, and structure. Observations of concretions, fossils,and other soil components were noted. Laboratory data included total carbon analysis, cation exchange capacity, percent base saturation, pH, particle size analysis, KCl total acidity, hydroxylamine-hydrochloride manganese, citrate-bicarbonate-dithionite iron, and Mehlich I extraction of eighteen elements. The soils in pedons 1 and 2 were classified as fine-silty, siliceous, thermic Fragic Paleudults. Pedons 3 and 8 were classified as fine-silty, siliceous, thermic Typic Paleudults. Pedons 4 and 7 were classified as fine-silty, siliceous, thermic Typic Hapludults. Parent material generally was loess over alluvium over residuum. Movement of soil solution nitrates and chlorides was influenced by soil texture, structure, chemical composition, and the presence of pans or discontinuities. Nitrates were concentrated in the horizons above a plow pan at approximately 28 centimeters and above a paleosol at approximately 85 centimeters. The nitrates were moving laterally downslope over the paleosol. Additions of high amounts of nitrogen had no direct correlation with soil solution nitrates. Long term additions of manure and fertilizer amendments influenced the chemical and physical composition of the soil. Total carbon was a good indicator of total nitrogen. A similar relationship was exhibited between Mehlich I extracted manganese and hydroxylamine hydrochloride extracted manganese. Long term management did influence soil morphology. Both management and morphology had an effect on concentration and distribution of nitrates as well as other chemical components in the soil

Protecting patient privacy when sharing patient-level data from clinical trials

Abstract Background Greater transparency and, in particular, sharing of patient-level data for further scientific research is an increasingly important topic for the pharmaceutical industry and other organisations who sponsor and conduct clinical trials as well as generally in the interests of patients participating in studies. A concern remains, however, over how to appropriately prepare and share clinical trial data with third party researchers, whilst maintaining patient confidentiality. Clinical trial datasets contain very detailed information on each participant. Risk to patient privacy can be mitigated by data reduction techniques. However, retention of data utility is important in order to allow meaningful scientific research. In addition, for clinical trial data, an excessive application of such techniques may pose a public health risk if misleading results are produced. After considering existing guidance, this article makes recommendations with the aim of promoting an approach that balances data utility and privacy risk and is applicable across clinical trial data holders. Discussion Our key recommendations are as follows: 1. Data anonymisation/de-identification: Data holders are responsible for generating de-identified datasets which are intended to offer increased protection for patient privacy through masking or generalisation of direct and some indirect identifiers. 2. Controlled access to data, including use of a data sharing agreement: A legally binding data sharing agreement should be in place, including agreements not to download or further share data and not to attempt to seek to identify patients. Appropriate levels of security should be used for transferring data or providing access; one solution is use of a secure ‘locked box’ system which provides additional safeguards. Summary This article provides recommendations on best practices to de-identify/anonymise clinical trial data for sharing with third-party researchers, as well as controlled access to data and data sharing agreements. The recommendations are applicable to all clinical trial data holders. Further work will be needed to identify and evaluate competing possibilities as regulations, attitudes to risk and technologies evolve

Advancing data science in drug development through an innovative computational framework for data sharing and statistical analysis

Background Novartis and the University of Oxford’s Big Data Institute (BDI) have established a research alliance with the aim to improve health care and drug development by making it more efficient and targeted. Using a combination of the latest statistical machine learning technology with an innovative IT platform developed to manage large volumes of anonymised data from numerous data sources and types we plan to identify novel patterns with clinical relevance which cannot be detected by humans alone to identify phenotypes and early predictors of patient disease activity and progression. Method The collaboration focuses on highly complex autoimmune diseases and develops a computational framework to assemble a research-ready dataset across numerous modalities. For the Multiple Sclerosis (MS) project, the collaboration has anonymised and integrated phase II to phase IV clinical and imaging trial data from ≈35,000 patients across all clinical phenotypes and collected in more than 2200 centres worldwide. For the “IL-17” project, the collaboration has anonymised and integrated clinical and imaging data from over 30 phase II and III Cosentyx clinical trials including more than 15,000 patients, suffering from four autoimmune disorders (Psoriasis, Axial Spondyloarthritis, Psoriatic arthritis (PsA) and Rheumatoid arthritis (RA)). Results A fundamental component of successful data analysis and the collaborative development of novel machine learning methods on these rich data sets has been the construction of a research informatics framework that can capture the data at regular intervals where images could be anonymised and integrated with the de-identified clinical data, quality controlled and compiled into a research-ready relational database which would then be available to multi-disciplinary analysts. The collaborative development from a group of software developers, data wranglers, statisticians, clinicians, and domain scientists across both organisations has been key. This framework is innovative, as it facilitates collaborative data management and makes a complicated clinical trial data set from a pharmaceutical company available to academic researchers who become associated with the project. Conclusions An informatics framework has been developed to capture clinical trial data into a pipeline of anonymisation, quality control, data exploration, and subsequent integration into a database. Establishing this framework has been integral to the development of analytical tools

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

EFSPI/PSI working group on data sharing: accessing and working with pharmaceutical clinical trial patient level datasets – a primer for academic researchers

Abstract Background Access to patient level datasets from clinical trial sponsors continues to be an important topic for the Pharmaceutical Industry as well as academic institutions and researchers. How to make access to patient level data actually happen raises many questions from the perspective of the researcher. Methods Patient level data access models of all major pharmaceutical companies were surveyed and recommendations made to guide academic researchers in the most efficient way through the process of requesting and accessing patient level data. Results The key considerations for researchers covered here are finding information; writing a research proposal to request data access; the review process; how data are shared; and the expectations of the data holder. A lot of clinical trial information is available on public registries and so these are great sources of information. Depending on the research proposal the required information may be available in Clinical Study Reports and therefore patient level data may not need to be requested. Many data sharing systems have an electronic form or template but in cases where these are not available the proposal needs to be created as a stand-alone document outlining the purpose, statistical analysis plan, identifying the studies for which data are required, the research team members involved, any conflicts of interest and the funding for the research. There are three main review processes - namely having an internal review board, external review board selected by the data holder or an external review board selected by a third party. Data can be shared through Open access i.e. on a public website, direct sharing between the data holder and the researcher, controlled access or the data holder identifies a contract organization to access the data and perform the analyses on behalf of the researcher. The data that are shared will have accompanying documentation to assist the researcher in understanding the original clinical trial and data collection methods. The data holder will require a legally binding data sharing agreement to be set up with the researcher. Additionally the data holder may be available to provide some support to the researcher if questions arise. Conclusion Whilst the benefits and value of patient level data sharing have yet to be fully realised, we hope that the information outlined in this article will encourage researchers to consider accessing and re-using clinical trial data to support their research questions

Best practice for analysis of shared clinical trial data

Abstract Background Greater transparency, including sharing of patient-level data for further research, is an increasingly important topic for organisations who sponsor, fund and conduct clinical trials. This is a major paradigm shift with the aim of maximising the value of patient-level data from clinical trials for the benefit of future patients and society. We consider the analysis of shared clinical trial data in three broad categories: (1) reanalysis - further investigation of the efficacy and safety of the randomized intervention, (2) meta-analysis, and (3) supplemental analysis for a research question that is not directly assessing the randomized intervention. Discussion In order to support appropriate interpretation and limit the risk of misleading findings, analysis of shared clinical trial data should have a pre-specified analysis plan. However, it is not generally possible to limit bias and control multiplicity to the extent that is possible in the original trial design, conduct and analysis, and this should be acknowledged and taken into account when interpreting results. We highlight a number of areas where specific considerations arise in planning, conducting, interpreting and reporting analyses of shared clinical trial data. A key issue is that that these analyses essentially share many of the limitations of any post hoc analyses beyond the original specified analyses. The use of individual patient data in meta-analysis can provide increased precision and reduce bias. Supplemental analyses are subject to many of the same issues that arise in broader epidemiological analyses. Specific discussion topics are addressed within each of these areas. Summary Increased provision of patient-level data from industry and academic-led clinical trials for secondary research can benefit future patients and society. Responsible data sharing, including transparency of the research objectives, analysis plans and of the results will support appropriate interpretation and help to address the risk of misleading results and avoid unfounded health scares