Population screening shows risk of inherited cancer and familial hypercholesterolemia in Oregon.

The Healthy Oregon Project (HOP) is a statewide effort that aims to build a large research repository and influence the health of Oregonians through providing no-cost genetic screening to participants for a next-generation sequencing 32-gene panel comprising genes related to inherited cancers and familial hypercholesterolemia. This type of unbiased population screening can detect at-risk individuals who may otherwise be missed by conventional medical approaches. However, challenges exist for this type of high-throughput testing in an academic setting, including developing a low-cost high-efficiency test and scaling up the clinical laboratory for processing large numbers of samples. Modifications to our academic clinical laboratory including efficient test design, robotics, and a streamlined analysis approach increased our ability to test more than 1,000 samples per month for HOP using only one dedicated HOP laboratory technologist. Additionally, enrollment using a HIPAA-compliant smartphone app and sample collection using mouthwash increased efficiency and reduced cost. Here, we present our experience three years into HOP and discuss the lessons learned, including our successes, challenges, opportunities, and future directions, as well as the genetic screening results for the first 13,670 participants tested. Overall, we have identified 730 pathogenic/likely pathogenic variants in 710 participants in 24 of the 32 genes on the panel. The carrier rate for pathogenic/likely pathogenic variants in the inherited cancer genes on the panel for an unselected population was 5.0% and for familial hypercholesterolemia was 0.3%. Our laboratory experience described here may provide a useful model for population screening projects in other states.

Can human nature be saved?

This paper argues that the best interpretation of the human nature concept used in evolutionary social science (ESS) is as the human adaptive complex. This understanding of the concept enables us to make sense of the features of human nature that are described in that literature as symptomatic of traits which are part of human nature, rather than being constitutive of human nature itself. This enables this proposal to make better sense of how the human nature concept is used than other current proposals for how to understand that concept.

Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies.

Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIA-accredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore current sources of discordance in classification. Eight laboratories each submitted 20 classified variants in the ACMG secondary finding v.2.0 genes. After removing duplicates, each of the 158 variants was annotated and independently classified by two additional laboratories using the ACMG-AMP guidelines. Overall concordance across three laboratories was assessed and discordant variants were reviewed via teleconference and email. The submitted variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and cardiac (27%) risk genes. Eighty-six (54%) variants reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance that could affect clinical recommendations (P/LP versus VUS/LB/B). 21% and 63% of variants submitted as P and LP, respectively, were discordant with VUS. Of the 54 originally discordant variants that underwent further review, 32 reached agreement, for a post-review concordance rate of 84% (118/140 variants). This project provides an updated estimate of variant concordance, identifies considerations for LP classified variants, and highlights ongoing sources of discordance. Continued and increased sharing of variant classifications and evidence across laboratories, and the ongoing work of ClinGen to provide general as well as gene- and disease-specific guidance, will lead to continued increases in concordance.

An age dependent response to hydroxyurea in pediatric sickle cell anemia patients with alpha thalassemia trait.

Hydroxyurea (HU) is a key drug therapy for individuals with sickle cell anemia (SCA), yet its clinical and hematologic responses can be variable. Various studies have reported the role of α-thalassemia as one of the most prevalent heritable traits that may modify HU response. We provide data from 62 pediatric and adolescent patients with SCA, 26 with co-inherited α-thalassemia trait. Our data suggest that altered hematologic and clinical responses to HU therapy are noted in adolescent SCA individuals with co-inherited α-thalassemia trait. Adolescent patients who co-inherited α-thalassemia trait had a greater reduction in vaso-occlusive episodes compared to those without α-thalassemia, despite a less robust fetal hemoglobin induction as well as a lower maximum HU dose. This clinical improvement was associated with a lower MCH and higher RBC count. Responses to HU in younger SCA children (ages 5-11years) with co-inherited α-thalassemia trait, compared to those without α-thalassemia trait, did not show any difference in number vaso-occlusive episodes, fetal hemoglobin induction and change in MCH and RBC count.

Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial.

The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging/magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ≥Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85%/79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities, which were associated with worse stenoses (incidence risk ratio [IRR] = 5.1, P ≤ .0001 and IRR = 4.1, P < .0001) than normal velocities; only 2% to 12% had any conditional/abnormal velocity. Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard/8 alternative arm subjects) had substantial parenchymal injury/vessel stenosis. At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis. SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980.

13-valent pneumococcal conjugate vaccine (PCV13) is immunogenic and safe in children 6-17 years of age with sickle cell disease previously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23): Results of a phase 3 study.

BACKGROUND: A large population of older children with sickle cell disease (SCD) is currently vaccinated with only 23-valent pneumococcal polysaccharide vaccine (PPSV23). In immunocompetent adults, PPSV23 vaccination reduces immune responses to subsequent vaccination with a pneumococcal vaccine. The 13-valent pneumococcal conjugate vaccine (PCV13), which addresses this limitation, may offer an advantage to this population at high risk of pneumococcal disease. PROCEDURE: Children with SCD 6-17 years of age previously vaccinated with PPSV23 at least 6 months before study enrollment received two doses of PCV13 6 months apart. Anti-pneumococcal polysaccharide immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured before, 1 month after each administration, and 1 year after the second administration. RESULTS: Following each PCV13 administration, IgG GMCs and OPA GMTs significantly increased, and antibody levels after doses 1 and 2 were generally comparable. Antibody levels declined over the year following dose 2. At 1 year after the second administration, OPA GMTs for all and IgG GMCs for most serotypes remained above pre-vaccination levels. Most adverse events were due to vaso-occlusive crises, a characteristic of the underlying condition of SCD. CONCLUSIONS: Children with SCD who were previously vaccinated with PPSV23 responded well to 1 PCV13 dose, and a second dose did not increase antibody response. PCV13 antibodies persisted above pre-vaccination levels for all serotypes 1 year after dose 2. Children with SCD may benefit from at least one dose of PCV13.

Challenging diagnosis and treatment of HIT in child with ventricular assistance device.

HIT presents the clinician with unique diagnostic challenges, especially in the pediatric population. The HIT clinical sequelae of thrombocytopenia and thrombosis are secondary to the activation of platelets by heparin-antibody complexes. Diagnosis involves clinical observations and confirmatory laboratory testing using antibody detection and the functional SRA. As we describe in the following case of a six-yr-old female, the SRA may be difficult to interpret in the case of high-titer antibodies and illustrates the need for repeat testing in cases of high clinical suspicion.

Genetic predictors for stroke in children with sickle cell anemia.

Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A(-) variant deficiency, and ß-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.

Stem cell transplant for children with sickle cell anemia: parent and patient interest.

We describe adolescents' and parents' interest in hematopoietic stem cell transplant (HSCT) as a cure for sickle cell disease (SCD) and factors associated with increased interest. We administered a 40 question survey to assess the interest in HSCT in parents and adolescents with HBSS or HBSß(0) thalassemia. The survey tool assessed factors that may influence interest in HSCT including demographic data, disease severity, views on prognosis, and health-related quality of life (HRQOL). All participants were given a handout on the risks and benefits of an HSCT before completing the survey. One hundred twenty-nine parents and 59 adolescents completed the survey. Forty-five percent of parents (54 of 119) would likely have their child undergo HSCT, and 35% of adolescents (19 of 55) would likely undergo HSCT if it was recommended by their hematologist. Parents of adolescents, as well as adolescent patients with better HRQOL, were more interested in HSCT. Prior exchange transfusion was associated with increased interest in HSCT (62% [23 of 37] versus 38% [29 of 76]; P = .02). The majority of parents believe their child's SCD will get better (66%; [80 of 122]), will not likely prevent their child from achieving life goals (83%; [100 of 121]), and will not shorten their child's lifespan (86%; [102 of 119]). There is strong parent and adolescent interest in HSCT as a cure for SCD. It is concerning that few parents and adolescents believe SCD will negatively impact their prognosis. Education on the potential long-term sequelae of SCD is needed when considering the role for HSCT.

Urinary transforming growth factor beta-1 as a marker of renal dysfunction in sickle cell disease.

Renal dysfunction affects 5-18% of patients with sickle cell disease (SCD). To date, no studies have described urinary levels of transforming growth factor ß-1 (TGF-ß1), a marker of fibrosis, and neutrophil gelatinase-associated lipocalin (NGAL), a marker of acute/chronic kidney disease, as biomarkers in identifying patients at risk of developing renal disease in SCD. We hypothesized that SCD subjects will have increased urinary excretion of TGF-ß1 and NGAL compared with healthy controls (CTR). We examined 51 SCD subjects: 42 HbSS, 8 HbSC, and 1 HbSD. Sixteen out of 42 patients with HbSS were on hydroxyurea (HU). Urinary excretion of TGF-ß1 was 26.4 ± 1.5 pg/mgCr in SCD subjects vs 15.0 ± 2.4 pg/mgCr in CTR (p<0.00001). SCD patients with hemoglobin < 9 g/dl had higher urinary TGF-ß1 than patients with milder anemia (p=0.002). Urinary TGF-ß1 trended lower in HbSS patients treated with HU (23.61 ± 2.6 pg/mgCr), vs patients not on HU (27.69 ± 1.8 pg/mgCr; p=0.055). There was no correlation between urinary TGF-ß1 and microalbuminuria or estimated glomerular function. There was no difference in urinary NGAL in SCD patients vs CTR. We suggest that urinary TGF-ß1 may serve as a marker of early renal injury in SCD.

How do specialist breast nurses help breast cancer patients at follow-up?

BACKGROUND: As the proportion of survivors from breast cancer increases it is possible that follow-up care could be delivered wholly by generalists to relieve over subscribed hospital clinics. However, guidelines seldom take into account the nature of interactions between patients and health care professionals involved in hospital-based follow-up. METHODS: Consultations between four Specialist Breast Nurses (SBNs) and 21 consecutive women attending a hospital-based breast cancer follow-up clinic in Western Australia were audio recorded and subjected to a thematic analysis. Recording of consultations ceased with saturation of themes. We analysed the data with reference to theoretical frameworks which postulate that social support is a powerful factor in determining positive health outcomes. We also drew on theories focusing on biographical disruption, biographical reinforcement and biographical reinvention. RESULTS: The majority of participants were Australian born, married women in their sixties. The mean duration of the consultations was 19 min (SD = 7.5, min = 8, max = 43.5). A core theme was the established relationship between the woman and her SBN. Overall, the SBNs played an important role in facilitating the transition of patients by supporting the woman in adjustment to a new self-image and bodily functioning. The SBN accompanies each woman through this phase in her life, white supporting a new narrative, promoting her 'rebirth' as someone with ideas, concerns and expectations that have altered significantly after the diagnosis of cancer. Five key themes emerged to demonstrate this supportive role: normalising; facilitating access to services; prevention; promoting self-esteem and promoting a proactive approach. CONCLUSIONS: Many women with breast cancer claimed a new perspective on what was now possible, acceptable or desirable in a host of life domains. Our data suggest that the follow-up care of cancer patients is more than just dealing with a checklist of symptoms but requires an understanding of the biographical disruption occasioned by a diagnosis of breast cancer.

An exploration of experiences of living renal donors following donation.

The experiences of living renal donors in Western Australia were explored using the qualitative method of grounded theory. Data were collected through 18 tape-recorded interviews with donors. Two main categories were identified that related to the physical and psychological reactions that occurred following surgery. This study provides insights (both positive and negative) into the donation experience.

Development of a donor driven assessment protocol in Western Australia based on experiences of living renal donors.

A new protocol for the selection and work-up of living renal donors has been developed in response to recent findings from a grounded theory study that explored the experiences of 18 donors in Western Australia. This protocol is designed to enhance the feelings of personal control by the donor over participation in the process and the potential outcome. It includes the coordination of the work-up process by a Clinical Nurse Consultant.

Candidate sequence variants and fetal hemoglobin in children with sickle cell disease treated with hydroxyurea.

BACKGROUND: Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. METHODOLOGY/PRINCIPAL FINDINGS: In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. CONCLUSIONS/SIGNIFICANCE: These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease.

On our best behavior: optimality models in human behavioral ecology.

This paper discusses problems associated with the use of optimality models in human behavioral ecology. Optimality models are used in both human and non-human animal behavioral ecology to test hypotheses about the conditions generating and maintaining behavioral strategies in populations via natural selection. The way optimality models are currently used in behavioral ecology faces significant problems, which are exacerbated by employing the so-called 'phenotypic gambit': that is, the bet that the psychological and inheritance mechanisms responsible for behavioral strategies will be straightforward. I argue that each of several different possible ways we might interpret how optimality models are being used for humans face similar and additional problems. I suggest some ways in which human behavioral ecologists might adjust how they employ optimality models; in particular, I urge the abandonment of the phenotypic gambit in the human case.

Chorea associated with antiphospholipid antibodies in a patient with Kabuki syndrome.

Kabuki syndrome, OMIM 147920 (KS) is a disorder characterized by multi-system abnormalities. These include physical, neurological, endocrine, and autoimmune abnormalities. Multiple autoimmune abnormalities are described in KS such as immune thrombocytopenic purpura (ITP), vitiligo, thyroiditis, hemolytic anemia, and hypogammaglobulinemia. In this report, we describe a patient with KS with sudden onset chorea associated with the presence of anti-phospholipid antibodies (aPLs) in the serum. Chorea in the presence of aPLs has been well described in the literature both in the presence and absence of antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). This report of APL in a patient with KS adds to the list of autoimmune disorders seen in patients with KS and also strengthens the hypothesis that patients with this syndrome have an increased incidence of immune dysregulation.

Management of prenatal care information: integration of the problem list and clinical comments.

To improve the functionality of our MAternal Record System (MARS), we reviewed the clinical problems entered into the MARS database from approximately 2800 patient records and interviewed representative clinicians about their use of the Clinical Comments and Problem List sections of MARS. Problems were assigned a unique term that corrected for spelling, spacing, synonyms, and abbreviation variations. Analysis of these terms suggested design changes that would increase the number of unique entries into the Problem List, including (1) modifications in the automated problem entry functions within MARS and (2) integration of the Problem List and Clinical Comments sections.

The continuum of maternal morbidity and mortality: factors associated with severity.

OBJECTIVE: The goal of this study was to examine whether sociodemographic, clinical, and other service-related factors, as well as preventability issues affect a woman's progression along the continuum of morbidity and mortality. STUDY DESIGN: This was a case-control study of pregnancy-related deaths, women with near-miss morbidity, and those with other severe, but not life threatening, morbidity. Factors associated with maternal outcome were examined. RESULTS: Provider factors (related to preventability) and clinical diagnosis were significantly associated with progression along the continuum after controlling for sociodemographic characteristics (P < .01 for both associations). CONCLUSION: In order to improve mortality rates, we must understand maternal morbidity and how it may lead to death. This study shows that important initiatives include addressing preventability, in particular, provider factors, which may play a role in moving women along the continuum of morbidity and mortality.

Alpha Thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia.

PURPOSE: Cerebrovascular complications of sickle cell disease (SCD) are common, but the risk factors remain unclear. The multicenter Stroke Prevention Trial in Sickle Cell Anemia (STOP) provided an opportunity to examine alpha thalassemia-2 as a modifying risk factor, using abnormal transcranial Doppler ultrasonography (TCD) as a surrogate marker for cerebrovascular disease. The authors hypothesized that children with abnormal TCD are less likely to have alpha thalassemia-2, and an increased hemoglobin level accounts for this protective effect. METHODS: A retrospective study was conducted of children with SCD who had both alpha gene and TCD data from STOP: 128 with TCD of at least 200 cm/s (abnormal TCD) and 172 with TCD less than 170 cm/s (normal TCD). RESULTS: Alpha thalassemia-2 was more frequent in the normal TCD group compared with the abnormal TCD group. The odds ratio for normal TCD and alpha thalassemia-2 was 4.1. Adjusting for either hemoglobin level or red cell size (mean corpuscular volume) reduced the odds ratio only slightly. Age, normal TCD, and alpha thalassemia-2 had significant statistical interaction, so that alpha thalassemia-2 was not related to TCD for age 10 years or older. CONCLUSIONS: The frequency of alpha thalassemia-2 was significantly higher in children with normal TCD. Speculation on mechanisms of effect includes improved erythrocyte deformability, reduced red cell adhesion, and reduced nitric oxide scavenging in alpha thalassemia-2. The association of alpha thalassemia-2 and normal TCD adds to the evidence on the protective effects of alpha thalassemia-2 in SCD and highlights the contribution of epistatic factors.