Big data, qualitative style: a breadth-and-depth method for working with large amounts of secondary qualitative data.

Archival storage of data sets from qualitative studies presents opportunities for combining small-scale data sets for reuse/secondary analysis. In this paper, we outline our approach to combining multiple qualitative data sets and explain why working with a corpus of 'big qual' data is a worthwhile endeavour. We present a new approach that iteratively combines recursive surface thematic mapping and in-depth interpretive work. Our breadth-and-depth method involves a series of steps: (1) surveying archived data sets to create a new assemblage of data; (2) recursive surface thematic mapping in dialogue with (3) preliminary 'test pit' analysis, remapping and repetition of preliminary analysis; and (4) in-depth analysis of the type that is familiar to most qualitative researchers. In so doing, we show how qualitative researchers can conduct 'big qual' analysis while retaining the distinctive order of knowledge about social processes that is the hallmark of rigorous qualitative research, with its integrity of attention to nuanced context and detail.

Tracing Ancient Human Migrations into Sahul Using Hepatitis B Virus Genomes.

The entry point and timing of ancient human migration into continental Sahul (the combined landmass of Australia, New Guinea, and Tasmania) are subject to debate. Unique strains of hepatitis B virus (HBV) are endemic among modern-day Australian Aboriginals (HBV/C4) and Indigenous Melanesians (HBV/C3). We postulated that HBV genomes could be used to infer human population movements because the main HBV transmission route in endemic populations is via mother-to-child for genotypes B and C infections. Phylogenetic and phylogeographic analyses of HBV genomes inferred the origin of HBV/C4 to be >59 thousand years ago (ka) (95% HPD: 34-85 ka), and most likely to have occurred on the Sunda Shelf (southeast extension of the continental shelf of Southeast Asia). Our analysis further suggested an age of >51 ka (95% Highest Posterior Density (HPD): 36-67 ka) for the most recent common ancestor of HBV/C4 in Australia, correlating with the arrival time of anatomically modern humans into Australia, with the entry point suggested along a southern route via Timor. While we also inferred the origin of HBC/C3 to be on the Sunda Shelf, our analyses suggested that it was carried into Melanesia by Indigenous Melanesians who migrated through New Guinea north of the highlands. These findings reveal that HBV genomes can be used to infer ancient human population movements.

Towards Genotype-Specific Care for Chronic Hepatitis B: The First 6 Years Follow Up From the CHARM Cohort Study.

OBJECTIVE: There is increasing evidence to suggest that, among those with chronic hepatitis B virus infection, the natural history and rate of progression to cirrhosis and hepatocellular carcinoma is influenced by hepatitis B virus genotype. The unique hepatitis B virus genotype C4 circulates among Indigenous Australians. The aim of this work is to describe the process of establishing this cohort and review the first 6 years of available data in an effort to understand the real-world clinical care and natural history of this subgenotype. METHOD: We followed a longitudinal cohort of Indigenous Australians from the Northern Territory of Australia with established subgenotype C4 infections. We assigned phases of disease according to Gastroenterological Society of Australia and Asian Pacific Association for the Study of the Liver criteria using clinical and laboratory information that had been collected for clinical management. RESULTS: Of 193 patients followed over a median of 38 months, 58 (30%) individuals transitioned from 1 disease phase to another, 10 (5%) cleared hepatitis B e antigen, and 6 cleared hepatitis B surface antigen (3%). In this relatively young cohort (median age 40.3 years), 26 (13%) had cirrhosis by the end of the follow up period, with the majority of these being in the immune control phase of disease. CONCLUSIONS: In this cohort of hepatitis B subgenotype C4 patients, we report an aggressive and dynamic clinical phenotype. High rates of cirrhosis at a young age appear to occur in the early phases of disease.

Molecular characterization of hepatitis B virus (HBV) in African children living in Australia identifies genotypes and variants associated with poor clinical outcome.

Migration from sub-Saharan Africa is contributing to the rising incidence of chronic hepatitis B (CHB) infection and its complications in Australia. African CHB is associated with unique genotypes, such as E and A1, which are associated with reduced vaccine efficacy and early-onset hepatocellular carcinoma, respectively, although the prevalence of these genotypes outside Africa is poorly described. Treatment-naïve children of African origin with CHB were recruited at the Royal Children's Hospital Melbourne. Population-based sequencing of the complete HBV genome, or the clinically relevant basal core promoter (BCP)/precore (PC) region, was performed, and the HBV genotype/subgenotype assigned by phylogenetic analysis. HBV was characterized in serum from 67 children, median age 12.5 years. HBV genotype E was most frequent (70 %), with genotype D [25 %; subgenotypes D6 (formerly D7)/D3/D2)] and subgenotype A1 (5 %) also being identified. Despite their young age, over 50 % of the children were HBeAg-negative and had seroconverted to anti-HBe, with this being associated with canonical BCP/PC mutations in the majority of cases. The profile of HBV in African children living in Australia was characterized by early HBeAg seroconversion and infection with HBV variants associated with poor clinical outcome, as well as genotypes previously associated with reduced vaccine efficacy or rapid progression to liver cancer. These findings have important ramifications for patient monitoring and treatment guidelines in the Australian paediatric setting.

ALT flares during nucleotide analogue therapy are associated with HBsAg loss in genotype A HBeAg-positive chronic hepatitis B.

BACKGROUND: Alanine aminotransferase (ALT) flares during NA therapy are uncommon but occur. Evaluation of ALT flares during nucleos(t)ide analogue (NA) therapy is important as new immunomodulatory therapies for hepatitis B virus (HBV) are developed. We evaluated the association between ALT flares and HBsAg loss during long-term therapy for genotype A CHB. METHODS: This analysis included genotype A subjects from a phase III study of tenofovir vs adefovir in HBeAg-positive HBV. ALT flare was defined as (i) a rise in ALT >2x ULN from normal ALT levels; or (ii) a rise in ALT >2x baseline ALT level. HBsAg response at week 384 was recorded as one of HBsAg loss vs HBsAg decline (≥1 log10  IU/mL decline) vs non-response. The primary analysis evaluated the association between ALT flare and HBsAg response. RESULTS: 54 subjects were included. 23/54 (43%) subjects experienced an on-treatment ALT flare. 45% achieved an HBsAg reduction ≥1 log10  IU/mL, and of these 67% achieved HBsAg loss at a median of 102 weeks [IQR: 64-156]. Flare was associated with HBsAg decline vs non-response (67% vs 23%, P = .002), and were more common in subjects who achieved HBsAg loss vs non-response (56% vs 23%), P = .049). There was a median delay of 56 weeks [IQR: 40-80] between a flare and HBsAg loss. CONCLUSION: In genotype A subjects undergoing long-term NA therapy, ALT flares predict for HBsAg response. The delay between ALT flare and HBsAg loss has implications for clinical trial design for early phase development of immunomodulatory strategies aiming for HBsAg loss.

Hepatitis B among immigrants from Myanmar: Genotypes and their clinical relevance.

Hepatitis B virus (HBV) from 76 adult immigrants in Australia from Myanmar was characterized to determine the prevalence of different HBV genotypes and subgenotypes. A mutational analysis was then performed to determine the presence of clinically significant mutations and correlate them to clinical outcomes. Initial genotyping revealed 68 patients with genotype C (89.5%) and eight patients with genotype B (10.5%). Phylogenetic analysis revealed the large majority of the genotype C infections were of subgenotype C1 (67/68). Sequencing of the HBV polymerase gene (and overlapping surface gene) revealed no mutations associated with antiviral resistance. HBV surface gene mutations were detected in 10 patients with subgenotype C1. HBV BCP/PC sequencing was obtained for 71/76 (93%) patients. BCP and/or PC mutations were identified in 57/71 (80%) of PCR positive patients. Treatment had been commenced for 15/76 (18%) patients, a further 26 untreated patients were in a stage of disease where HBV treatment would be considered standard of care. It was identified that genotype C1 is the predominant sub-genotype in this population. Genotype C is known to be associated with increased risk of development of HCC. This highlights the need for screening for HCC given the potential for the development of liver cancer. It was also identified that people with HBV were potentially not receiving optimal therapy in a timely fashion.

How paradata can illuminate technical, social and professional role changes between the Poverty in the UK (1967/1968) and Poverty and Social Exclusion in the UK (2012) surveys.

This article brings together analyses of the micro paradata 'by-products' from the 1967/1968 Poverty in the United Kingdom (PinUK) and 2012 Poverty and Social Exclusion in the UK (PSE) surveys to explore changes in the conditions of production over this 45 year period. We highlight technical, social and professional role continuities and changes, shaped by the institutionalisation of survey researchers, the professionalization of the field interviewer, and economisation. While there are similarities between the surveys in that field interviewers were and are at the bottom of the research hierarchy, we demonstrate an increasing segregation between the core research team and field interviewers. In PinUK the field interviewers are visible in the paper survey booklets; through their handwritten notes on codes and in written marginalia they can 'talk' to the central research team. In PSE they are absent from the computer mediated data, and from communication with the central team. We argue that, while there have been other benefits to field interviewers, their relational labour has become less visible in a shift from the exercise of observational judgement to an emphasis on standardisation. Yet, analyses of what field interviewers actually do show that they still need to deploy the same interpersonal skills and resourcefulness to secure and maintain interviews as they did 45 years previously.

Deep sequencing shows that HBV basal core promoter and precore variants reduce the likelihood of HBsAg loss following tenofovir disoproxil fumarate therapy in HBeAg-positive chronic hepatitis B.

OBJECTIVE: Hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) loss are important clinical outcomes for patients with chronic hepatitis B (CHB) treated with antiviral therapy. To date, there have been few studies that have evaluated viral sequence markers predicting serological response to nucleos(t)ide analogue (NA) treatment. DESIGN: We used next-generation sequencing (NGS) and quantitative HBV serology (HBeAg and HBsAg) to identify viral sequence markers associated with serological response to long-term tenofovir disoproxil fumarate therapy among HBeAg-positive patients. In the GS-US-174-0103 study, approximately half the patients seroconverted to anti-HBe by week 192 and 11% of patients exhibited HBsAg loss, the closest outcome to functional cure. The frequency of HBV variants that have previously been associated with HBV clinical outcomes was evaluated. HBV viral diversity in baseline sequences generated by NGS was calculated using Shannon entropy. RESULTS: NGS analysis of HBV sequences from 157 patients infected with genotypes A to D showed the frequency of variants in the basal core promoter (BCP) and precore (PC) regions varied by genotype and that these mutations were associated with the absence of HBsAg loss. This was the case even when mutations were present at frequencies below the threshold of detection by population sequencing. Increased viral diversity across the HBV genome as determined by NGS was also associated with reduced likelihood of HBsAg loss. CONCLUSION: Patients with detectable BCP and/or PC variants and higher viral diversity have a lower probability of HBsAg loss during long-term NA therapy. Strategies to achieve functional cure of HBV infection through combination therapy should consider using NGS to stratify patients according to BCP/PC sequence. Consideration should also be given to earlier initiation of therapy prior to the emergence of BCP/PC variants. TRIAL REGISTRATION NUMBER: NCT00116805; Post result.

Genotypic profiles of hepatitis B in African immigrants and their clinical relevance.

Hepatitis B virus (HBV) from 40 adult African immigrants in Australia was characterized to determine the prevalence of different HBV genotypes and subgenotypes. A mutational analysis was then performed to determine the presence of clinically significant mutations and correlate them to clinical outcomes. Initial sequencing analysis revealed 13 with genotype A (32.5%), 13 with genotype D (32.5%), and 14 with genotype E (35%). Serology showed that 37 were HBeAg negative. Phylogenetic analysis identified a high prevalence (25%) of HBV subgenotype A1 in our cohort, a subgenotype which has been associated with more aggressive clinical disease. BCP/PC sequencing was obtained for 38 patients. BCP and/or PC mutations were identified in 36/38 (95%). The median viral load of all patients was 2995 IU/mL and most of the pathology results were within the normal range. Only one patient had an increased APRI score of 1.1 suggestive of cirrhosis. We present novel information on the HBV genotypes amongst the African population in Australia along with clinical correlates. The high prevalence of A1 subgenotype in this population supports the current Australian recommendation to commence hepatocellular carcinoma screening in Africans with chronic HBV from 20 years old.

Molecular epidemiology of hepatitis delta virus in the Western Pacific region.

BACKGROUND: Hepatitis delta virus (HDV) is a defective RNA virus requiring the presence of the hepatitis B virus (HBV) for the completion of its life cycle. Active replication of HDV can lead to severe hepatitis, and although present worldwide has an irregular geographical distribution, especially in the Asian Pacific region. OBJECTIVES: The aim of this study was to determine the prevalence and molecular epidemiology of HDV isolates in Oceania following the 1998 evaluation of the hepatitis B vaccine program. STUDY DESIGN: Sera collected from 184 hepatitis B surface antigen (HBsAg) positive Pacific Islanders living in Micronesia, Polynesia and Melanesia were tested for HDV RNA. RESULTS: Twenty of 54 patients with chronic hepatitis B (CHB) from Kiribati were positive for serum HDV RNA (37%), whilst sera from patients with CHB from Tonga (59), Fiji (42) and Vanuatu (29) were negative. The mean HDV RNA load for the 20 samples was 7.00log10copies/mL. Phylogenetic analysis revealed that the Kiribati HDV isolates were of genotype 1 and clustered with a previously published isolate from Nauru forming a distinct clade of Pacific HDV. All Micronesian isolates contained a serine at codon 202 of large hepatitis delta antigen (L-HDAg) demonstrating possible relatedness to strains of HDV-1 of African origin. CONCLUSIONS: This study has confirmed endemic HDV infection in Micronesia and identified Kiribati as having amongst the highest prevalence for HDV viraemia in patients with CHB. Further investigations are ongoing into the origins of this unique HDV Pacific strain, and its inter-relationship with HBV.

The politics of concepts: family and its (putative) replacements.

The central concern of this paper is that there has been a move within British sociology to subsume (or sometimes, even replace) the concept of 'family' within ideas about personal life, intimacy and kinship. It calls attention to what will be lost sight of by this conceptual move: an understanding of the collective whole beyond the aggregation of individuals; the creation of lacunae that will be (partially) filled by other disciplines; and engagement with policy developments and professional practices that focus on 'family' as a core, institutionalized, idea. While repudiating the necessity (and indeed, pointing out the dangers) of providing any definitive answer to definitions of 'family', the paper calls for critical reflection on the implications of these conceptual moves.

Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase.

BACKGROUND & AIMS: Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo-controlled 48-week studies with this drug. The aim of this study was to characterize adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment. METHODS: HBV DNA was PCR amplified and sequenced. Phenotypic studies used patient-derived HBV as well as specific mutations created by site-directed mutagenesis of a HBV/baculovirus recombinant. RESULTS: Following the commencement of treatment with adefovir dipivoxil, the patient initially responded with a 2.4 log(10) decrease in serum HBV DNA and normalization of alanine aminotransaminase levels by week 16. During the second year of treatment, however, serum HBV DNA rose progressively, eventually returning to near-pretreatment levels. This increase in viral replication was associated with a marked increase in alanine aminotransferase and mild changes in bilirubin, albumin, and prothrombin time. Comparison of pretreatment and posttreatment HBV DNA by polymerase chain reaction sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase. In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient-derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to adefovir. CONCLUSIONS: The development of this novel mutation in the HBV polymerase confers resistance to adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, achieving normalization of alanine aminotransferase and a significant decrease in serum HBV DNA.