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At least 307 records · Page 17Linked to original sources
PubMed2003

Access to emergency contraception.

The merits of non-prescription distribution of levonorgestrel as emergency contraception (EC), which is effective within 72 hours of unprotected intercourse, are contentious. The advantage of promptness and convenience of access may be offset by the absence of medical counselling. Opposition to EC based on the possibility of the drug acting after fertilization but before implantation departs from standard medical criteria of pregnancy. Physicians who propose to apply non-medical criteria, and use religious objections to abortion to deny prescription of EC, must publicize their opposition in advance, so that women may seek assistance elsewhere. When objecting practitioners, or facilities, become responsible for women for whom EC is indicated, such as rape victims, they are bound ethically and legally to refer them to reasonably accessible non-objecting sources of care.

Adult↗
PubMed2003

Invited review: bovine studies on optimal lengths of dry periods.

Milk production per cow has increased as a result of progressive changes in the genetics and management of the dairy animal population. A management constant during many decades of progress has been the widely adopted dry period length of 51 to 60 d. The scientific basis for that industry standard was examined to assess its validity as the appropriate standard for the modern dairy industry. If subsequent milk yields can be sustained fully after dry periods that are shorter than the current standard, then considerable milk is being forfeited by retaining longer dry periods. Conversely, failure to allow any dry period will result in a significant decrease in subsequent milk synthesis and secretion. Most studies to determine the minimum length of dry period required have involved retrospective analyses of observational data. Only five experiments have been reported in which dairy cows were assigned, at random, to planned 30- and 60-d dry periods. Estimates of the change in subsequent milk production when days dry were decreased from 50 to 57 d to 30 to 34 d ranged from a 10% decrease to a 1% increase. However, lower yields after shorter dry periods may be partially offset by greater milk yields in the previous lactation if such cows are milked 3 to 4 wk longer. Environmental factors that influence milk production as well as the biological processes that occur within the mammary gland during the nonlactating period must be considered when dry period lengths are compared. Importantly, additional animal trials that specifically assign cows randomly to the dry period lengths to be evaluated are needed to determine optimal dry period lengths for modern dairy cows in differing management scenarios.

Animals↗
PubMed1990

A Neurospora crassa ribosomal protein gene, homologous to yeast CRY1, contains sequences potentially coordinating its transcription with rRNA genes.

We have isolated and sequenced a Neurospora crassa ribosomal protein gene (designated crp-2) strongly homologous to the rp59 gene (CRY1) of yeast and the S14 ribosomal protein gene of mammals. The inferred sequence of the crp-2 protein is more homologous (83%) to the mammalian S14 sequence than to the yeast rp59 sequence (69%). The gene has three intervening sequences (IVSs) two of which are offset 7 bp from the position of IVSs in the mammalian genes. None correspond to the position of the IVS in the yeast gene. Crp-2 was mapped by RFLP analysis to the right arm of linkage group III. The 5' region of the gene contains three copies of a sequence, the Ribo box, previously shown to be required for transcription of both 5S and 40S rRNA genes. We speculate that the Ribo box may coordinate ribosomal protein and rRNA gene transcription.

Amino Acid Sequence↗
PubMed2006

PAX2 is reactivated in urinary tract obstruction and partially protects collecting duct cells from programmed cell death.

Obstruction of the urinary tract activates apoptotic pathways in collecting duct cells and leads to loss of renal parenchyma before surgical intervention. It has been suggested that developmental pathways may be reactivated to offset acute organ damage. One such molecule, PAX2, is expressed throughout the fetal collecting duct and was recently shown to suppress apoptosis during kidney development. We hypothesized that acute unilateral urinary tract obstruction (UUO) reactivates PAX2 expression in the mature kidney and partially suppresses apoptosis. If so, animals with PAX2 mutations should have increased susceptibility to parenchymal damage. Wild-type and heterozygous Pax2 mutant (C3H/Pax2(1Neu)) mice underwent unilateral ureteric ligation or sham operation at 6 wk of age; kidneys were examined after 5, 10, and 15 days. Whereas PAX2 protein levels fell to low levels in the first weeks of life, it was sharply reactivated by day 10 in collecting duct cells of wild-type but not in Pax2(1Neu) mutant mice with UUO. Wild-type mice with UUO had marked TUNEL and cleaved spectrin staining in tubular cells and reduced kidney weight after 10-15 days. Mutant mice had exaggerated increases in markers of apoptosis and exaggerated loss of renal parenchymal loss in the obstructed kidney. These observations suggest that PAX2 is rapidly reactivated in UUO and that mice with genetically limited PAX2 expression have heightened susceptibility to apoptosis.

Animals↗
PubMed2006

The impact of controlled nutrition during the dry period on dairy cow health, fertility and performance.

Average dairy herd fertility is declining, with more serves per successful conception, extended calving intervals and increased culling due to failure to rebreed, all adding significant costs to milk production. Genetics, management and nutrition have all contributed to this decline in fertility; the paper focuses primarily on nutritional issues. The extent of body condition loss after calving and its possible impact on fertility is considered, with evidence that this phenomenon is common in many herds irrespective of average milk yields. Body tissue mobilisation after calving increases the flux of non-esterified fatty acids to the liver and pathways of fatty acid metabolism are considered. Particular attention is given to the effects of high plasma non-esterified fatty acid levels on fat accumulation in liver cells and possible impacts on nitrogen and glucose metabolism. Current nutritional practices with early lactation cows which aim to stimulate milk yield and peak milk production but have been shown to exacerbate body condition loss, are reviewed. The paper also considers cow health issues during the peri-parturient period and how these may affect milk yield and fertility. It is concluded that current feeding practices for dry cows, with the provision of increasing amounts of the lactation ration during the Close-up period to accustom the rumen microbes and offset the expected reduction in feed intake as pregnancy reaches term, have largely failed to overcome peri-parturient health problems, excessive body condition loss after calving or declining fertility. From an examination of the energy and protein requirements of dry cows, it is suggested that current Close-up feeding practices can lead to luxury intakes of nutrients that can increase fat deposition in the viscera and the liver. Under such conditions, metabolism of nutrients by the cow may be compromised. In contrast, limited feeding throughout the whole dry period has been shown to prevent many of the problems which can affect peri-parturient cows. A new feeding strategy based on a low energy: high fibre ration (9 MJ metabolisable energy and 130 g crude protein/kg ration dry matter) containing high levels of chopped straw and offered ad libitum as a total mixed ration throughout the whole dry period is proposed. The performance of 32 dairy farms in France where this strategy has been adopted for at least 3 years is provided, with positive outcomes now being obtained by UK and Irish dairy farmers. Independent US research evidence has confirmed some of these benefits whilst limited data on cow fertility is presented. It is hypothesised that luxury feeding during the dry period can cause cows to become insulin resistant leading to an increased risk of type II diabetes. Such cows are likely to have poorer fertility whilst possible mechanisms which increase the risk of peri-parturient health problems are discussed. Further research to understand the mechanisms of these effects is required and is currently ongoing. However the magnitude of the effects noted on an increasing number of dairy farms suggests this approach to feeding the dry cow is capable of bringing real benefits to many dairy herds in terms of fewer health problems, reduced body condition loss and improved fertility.

Animal Feed↗
PubMed2001

Alanine-scanning mutagenesis of the small-subunit beta A-beta B loop of chloroplast ribulose-1,5-bisphosphate carboxylase/oxygenase: substitution at Arg-71 affects thermal stability and CO2/O2 specificity.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) enzymes from different species differ with respect to carboxylation catalytic efficiency and CO2/O2 specificity, but the structural basis for these differences is not known. Whereas much is known about the chloroplast-encoded large subunit, which contains the alpha/beta-barrel active site, much less is known about the role of the nuclear-encoded small subunit in Rubisco structure and function. In particular, a loop between beta-strands A and B contains 21 or more residues in plants and green algae, but only 10 residues in prokaryotes and nongreen algae. To determine the significance of these additional residues, a mutant of the green alga Chlamydomonas reinhardtii, which lacks both small-subunit genes, was used as a host for transformation with directed-mutant genes. Although previous studies had indicated that the betaA-betaB loop was essential for holoenzyme assembly, Ala substitutions at residues conserved among land plants and algae (Arg-59, Tyr-67, Tyr-68, Asp-69, and Arg-71) failed to block assembly or eliminate function. Only the Arg-71 --> Ala substitution causes a substantial decrease in holoenzyme thermal stability. Tyr-68 --> Ala and Asp-69 --> Ala enzymes have lower K(m)(CO2) values, but these improvements are offset by decreases in carboxylation V(max) values. The Arg-71 --> Ala enzyme has a decreased carboxylation V(max) and increased K(m)(CO2) and K(m)(O2) values, which account for an observed 8% decrease in CO2/O2 specificity. Despite the fact that Arg-71 is more than 20 A from the large-subunit active site, it is apparent that the small-subunit betaA-betaB loop region can influence catalytic efficiency and CO2/O2 specificity.

Amino Acid Sequence↗
PubMed2002

Pathogenesis of bone fragility in women and men.

There is no one cause of bone fragility; genetic and environmental factors play a part in development of smaller bones, fewer or thinner trabeculae, and thin cortices, all of which result in low peak bone density. Material and structural strength is maintained in early adulthood by remodelling; the focal replacement of old with new bone. However, as age advances less new bone is formed than resorbed in each site remodelled, producing bone loss and structural damage. In women, menopause-related oestrogen deficiency increases remodelling, and at each remodelled site more bone is resorbed and less is formed, accelerating bone loss and causing trabecular thinning and disconnection, cortical thinning and porosity. There is no equivalent midlife event in men, though reduced bone formation and subsequent trabecular and cortical thinning do result in bone loss. Hypogonadism contributes to bone loss in 20-30% of elderly men, and in both sexes hyperparathyroidism secondary to calcium malabsorption increases remodelling, worsening the cortical thinning and porosity and predisposing to hip fractures. Concurrent bone formation on the outer (periosteal) cortical bone surface during ageing partly compensates for bone loss and is greater in men than in women, so internal bone loss is better offset in men. More women than men sustain fractures because their smaller skeleton incurs greater architectural damage and adapts less effectively by periosteal bone formation. The structural basis of bone fragility is determined before birth, takes root during growth, and gains full expression during ageing in both sexes.

Adolescent↗
PubMed1990

Use and perceived attributes of cruciferous vegetables in terms of genetically-mediated taste sensitivity.

Bitter tasting compounds in cruciferous vegetables resemble chemically the compound phenylthiocarbamide (PTC). As sensitivity to PTC is genetically mediated, it was hypothesized that this characteristic would be linked to greater sensitivity of the bitter tasting components in cruciferous vegetables, and that PTC sensitivity would be reflected in less favourable sensory perceptions and lower use of the vegetables. PTC status was determined for healthy, racially and culturally similar women, alike in foodways and aged 18-46 years. The frequency of use and perceptions of sensory, post-ingestional and social attributes of 11 cruciferous and two non-cruciferous vegetables in both raw and cooked forms were compared between the PTC tasters and non-tasters. Minimal effects of PTC status on these factors were observed. Only two vegetables showed significant differences in use--PTC non-tasters used cooked turnip and raw watercress significantly more than did PTC tasters. Perceived bitter taste and aroma did not offer an explanation for the findings. Similarly, familiarity, early exposure, and tolerance did not account for any group differences. PTC status, especially in terms of non-tasting propensity, may have some sensory-specific effects which will impact on the use of cruciferous vegetables by young and mature women, but environmental factors may offset this effect and must be considered in studies of food behaviour.

Adolescent↗
PubMed2002

Evolutionary speed limits inferred from the fossil record.

The dynamics of extinction and diversification determine the long-term effects of extinction episodes. If rapid bursts of extinction are offset by equally rapid bursts of diversification, their biodiversity consequences will be transient. But if diversification rates cannot accelerate rapidly enough, pulses of extinction will lead to long-lasting depletion of biodiversity. Here I use spectral analysis of the fossil record to test whether diversification rates can accelerate as much as extinction rates, over both short and long spans of geological time. I show that although the long-wavelength variability of diversification rates equals or exceeds that of extinctions, diversification rates are markedly less variable than extinction rates at wavelengths shorter than roughly 25 million years. This implies that there are intrinsic speed limits that constrain how rapidly diversification rates can accelerate in response to pulses of extinction.

Animals↗
PubMed2006

Estimating the value of novel interventions for Parkinson's disease: an early decision-making model with application to dopamine cell replacement.

A long-term cost-effectiveness model for early decision-making and estimation of outcomes of novel therapeutic procedures for Parkinson's disease (PD) was developed based on the Hoehn and Yahr (HY) stages of PD. Results provided support for model validity. Model application to a future dopamine cell replacement therapy indicated long-term cost offsets and gains in quality-adjusted life years (QALYs) in early onset PD (HY III-IV), as compared to standard drug therapy. The maximum price premium (i.e., profit or compensation for developmental costs) for the intervention to remain cost-effective was estimated to euro12000-64000 according to cost-per-QALY thresholds of euro38000-70000 and depending on whether all or only medical direct costs are considered. The study illustrates the value of early health economic modeling and the described model shows promise as a means to estimate outcomes and aid decision-making regarding novel interventions for PD.

Adult↗
PubMed1993

Identification of a DNA structural motif that includes the binding sites for Sp1, p53 and GA-binding protein.

We have analyzed predicted helical twist angles in the 21-bp repeat region of the SV40 genome, using a semi-empirical model previously shown to accurately predict backbone conformations. Unexpectedly, the pattern of twist angles characteristic of the six GC-boxes is repeated an additional five times at positions that are regularly interspersed with the six GC-box sequences. These patterns of helical twist angles are associated with a second, imperfectly-repeated sequence motif, the TR-box 5'-RRNTRGG. Unrelated DNA sequences that interact with trans-acting factors (p53 and GABP) exhibit similar twist angle patterns, due to elements of the general form 5'-RRRYRRR that occur as interspersed arrays with a spacing of 10-11 bp and an offset of 4-6 bp. Arrays of these elements, which we call pyrimidine sandwich elements (PSEs), may play an important role in the interaction of trans-acting factors with DNA control regions. In 13 human proto-oncogenes analyzed, we identified 31 PSE arrays, 11 of which were in the 5'-flanking regions of the genes. The most extensive array was found in the promoter region of the K-ras gene. Extending over 80 bp of DNA, it contained 16 PSEs that showed an average deviation from the SV40 criterion pattern of angles of only 1.2 degrees.

Base Sequence↗
PubMed1995

Sequence-specific covalent modification of DNA by cross-linking oligonucleotides. Catalysis by RecA and implication for the mechanism of synaptic joint formation.

Oligodeoxynucleotides (ODNs) were conjugated to chlorambucil and used as affinity labeling reagents to study joint molecule formation by the Escherichia coli recombinase recA. Chlorambucil is a bifunctional nitrogen mustard which alkylates the N-7 position of guanine in the major groove of double-stranded DNA (dsDNA). Incoming ODNs at least 30 nucleotides long cross-linked to a long homologous duplex DNA in the presence of recA and ATP gamma S. Efficient cross-linkage to the complementary recipient strand of the joint occurred preferentially at guanines positioned 5' relative to the appended chlorambucil group. The pattern of recipient strand alkylation was identical to that observed within a protein-free duplex and indicated that strand exchange had occurred prior to alkylation. Modification of the outgoing homologous strand of the joint was less efficient and spanned a 15-20 nucleotide long region offset to the 3' side of the tethered chlorambucil. Alkylation of both recipient and outgoing strands in the same joint molecule occurred with low frequency. By contrast, no affinity alkylation of the displaced strand was observed within a synthetic D-loop. These reaction patterns suggest that the incoming ODN approaches from the minor groove of the duplex to yield a poststrand exchange joint in which the major groove of the newly formed heteroduplex harbors the outgoing strand in an unpaired state. No evidence was obtained for the involvement of a triple-stranded DNA intermediate in recombination.

Affinity Labels↗
PubMed1994

Chronobiological analysis of a new clock mutant, Toki, in Drosophila melanogaster.

We have isolated a new semidominant clock mutant Toki on the second chromosome in Drosophila melanogaster. This mutant differs from the wild-type Canton-S in several properties as follows. Larger values are obtained in the phase angle difference (phi, the time from lights-off in a 24-hr light-dark cycle to an activity offset), the ratio of activity time to rest time (alpha/rho) and the activity level. The free-running period (tau) is 25.3 hr, one hour longer than in the wild-type. In the phase response curve (PRC), the ratio between the delay and the advance portion is larger and the cross-over point occurs later, although there is no difference in amplitude of the mutant's PRC (Type I). The rhythm is more sensitive to the light intensity, becoming obscure in darker condition. Toki interacts with other clock mutations, pers, perL and And, in such a way that tau s associated with these three X-linked mutations are lengthened and phi values become smaller.

Analysis of Variance↗
PubMedDate not supplied

Autosomal dominant non-syndromal low-frequency sensorineural hearing impairment linked to chromosome 4p16 (DFNA14): statistical analysis of hearing threshold in relation to age and evaluation of vestibulo-ocular functions.

A Dutch kindred was studied with low-frequency sensorineural hearing impairment linked to a new locus on chromosome 4p16 (DFNA14). Of the affected individuals, 21 (aged 11-75 years) were examined and the most recent audiogram was used for cross-sectional analysis of hearing threshold in relation to age. Suitable serial audiograms were available for a longitudinal analysis in nine cases: they had been obtained from the age of six years onwards and covered a follow-up period from 14 to 36 years. The presumably congenital (offset) component of SNHI was extrapolated or estimated from average values and offset thresholds were found of about 45 dB at 0.25-1 kHz, 25 dB at 2 kHz and 10 dB at 4-8 kHz. Significant progression in hearing impairment occurred at all frequencies, but could be attributed to presbyacusis. The combination of congenital, stationary low-frequency SNHI and presbyacusis resulted in an up-sloping audiogram in the first five decades of life, which evolved into a flat-type audiogram in the sixth or seventh decade and a down-sloping audiogram at a more advanced age. With few exceptions, vestibular function was intact.

Adolescent↗
PubMed1999

The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series.

CONTEXT: A recent collaborative study found that apolipoprotein E (APOE) genotype, in conjunction with the clinical diagnosis of Alzheimer disease (AD), was useful in improving diagnostic specificity (correctly not diagnosing AD) relative to the clinical diagnosis alone. Since these samples are particularly enriched with patients with AD and the APOE epsilon4 allele, results may not be generalizable to patients seen in the general medical community. OBJECTIVE: To evaluate the diagnostic utility of the APOE genotype in diagnosing AD in a community-based case series from the largest health maintenance organization in an urban area. DESIGN: We examined the effect of including APOE genotype on the diagnosis of AD in a community-based case series of patients presenting with memory complaints. PATIENTS: Clinical and neuropathologic diagnoses and APOE genotype were obtained from 132 patients who underwent evaluation for dementia and subsequent autopsy. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values given various combinations of clinical diagnoses and the presence of an APOE epsilon4 allele. RESULTS: Of the 132 patients, 94 had neuropathologically confirmed AD, yielding a prevalence of 71%. The clinical diagnosis alone yielded a sensitivity of 84%, an estimated specificity of 50%, and positive and negative predictive values of 81% and 56%, respectively. The presence of an epsilon4 allele alone was associated with an estimated sensitivity of 59%, specificity of 71%, and positive and negative predictive values of 83% and 41%, respectively. Using the presence of clinical AD and an epsilon4 allele decreased the sensitivity to 49% and increased the specificity to 84%. The positive and negative predictive values were 88% and 40%, respectively. Alternatively, the clinical diagnosis of AD or the presence of an epsilon4 allele in individuals not meeting clinical criteria for AD increases the estimated sensitivity to 94% but decreases the specificity to 37%. The positive and negative predictive values were 79% and 70%, respectively. The changes in the sensitivity and specificity for the combined tests relative to clinical diagnosis alone offset each other. For lower prevalence communities, the positive predictive value will be much lower than those observed herein. CONCLUSIONS: Our findings do not support the use of APOE genotyping alone in the diagnosis of AD in the general medical community. Although the presence of an epsilon4 allele in older persons with clinical AD increased the probability of having AD and the absence of an epsilon4 allele in this group decreased the probability of having AD, the association is not strong enough in the differential diagnosis of non-Alzheimer dementia and AD.

Aged↗
PubMed2005

Linear independence of pairwise comparisons of DNA microarray data.

MOTIVATION: For DNA microarrays, the gain in certainty by performing multiple experimental repeats is offset by the high cost of each experiment. In a typical experiment, two independent measurements (that is, data from two separate arrays) are combined to yield a single comparative index per gene. Thus, although one uses 2n arrays and performs 2n independent measurements, one obtains only n comparative measurements. We addressed the question: how many of the potential n2 comparisons derivable from such data are actually independent, and what effect do these additional comparisons have on the false positive rate. RESULTS: We show there are precisely 2n - 1 independent comparisons available from among the n2 possibilities. Applying these additional n - 1 independent comparisons to experimental and simulated data reduced the false positive rate by as much as 10-fold, with excellent agreement between experimental and theoretical false positive rates.

Algorithms↗
PubMed2003

Tandem electrostatic effect from the first to the third aglycon in the trimeric RNA owing to the nearest-neighbor interaction.

We here show an electrostatic polar-pi interaction from the first to the third aglycon, via the second aglycon, in the ground state in two single stranded trimeric RNAs, 5'-GpA(1)pA(2)-3' (3) and 5'-GpApC-3' (4), as a result of intramolecular nearest neighbor offset-stacking. The experimental evidence in support of this conclusion has been obtained by comparing the pK(a)s of each aglycone in the two trimers with those of guanosine 3'-ethyl phosphate, GpEt (1) and 5'-GpA-3' (2): Thus, the pK(a) of N(1)-H of guanin-9-yl of 5'-GpA(1)pA(2)-3' (3) could be measured by pH titration (pH 7.3-11.6) of its own deltaH8G (pK(a) 9.75 +/- 0.02) as well as from deltaH8A(1) (pK(a) 9.72 +/- 0.02) and deltaH2A(1) (pK(a) 9.83 +/- 0.04) of the neighboring pA(1)p moiety and the deltaH8A(2) (pK(a) 9.83 +/- 0.02) of the terminal pA(2) moiety. Similarly, the pH titration of GpApC (4) shows the pK(a) of N(1)-H of guanin-9-yl from its own deltaH8G (pK(a) 9.88 +/- 0.03) as well as from deltaH8A (pK(a) 9.87 +/- 0.01) of the neighboring pAp moiety, and deltaH5/H6C (pK(a) 9.88 +/- 0.01 and 9.90 +/- 0.01 respectively) of the 3'-terminal cytosin-1-yl. This intramolecular nearest neighbor electrostatic interaction in the single-stranded RNA modulates the pseudoaromaticity of the nearest neighbors by almost total transmission of because they constitute an extended array of offset-stacked coupled aromatic heterocycles within a polyanionic sugar-phosphate backbone at the ground state. The enhanced basicity of Gp residue by ca. 0.6 pK(a) unit in the trimers compared to that of the dimer is a result of the change in the electrostatic microenvironment owing to the nearest neighbors in the former (the nucleobases as well as the phosphates). Thus, the from the 5'-guanylate ion to the 3'-end aglycon via the central adenin-9-yl is 55 to 56 kJ mol(-)(1) in each step through a distance spanning approximately 6.8 A in an unfolded state. As a result, the pK(a) of guanin-9-yl moiety has become 9.25 +/- 0.02 in GpEt (1), 9.17 +/- 0.02 in GpA (2), 9.75 +/- 0.02 in GpApA (3), and 9.88 +/- 0.03 in GpApC (4). This means that guanin-9-yl moiety of trimers 3 and 4 is more basic than in the monomer or the dimer. The net outcome of this electrostatic cross-talk between the two neighboring heterocycles is creation of new hybrid aglycones in an oligo or polynucleotide, whose physicochemical property and the pseudoaromatic character are completely dependent both upon the nearest neighbors, and whether they are stacked or unstacked. Thus, this tunable physicochemical property of an aglycon (an array of the extended genetic code) may have considerable implication in our understanding of the specific ligand binding ability of an aptamer, the pK(a) and the hydrogen bonding ability of nucleic acids in a microenvironment, or in the triplet usage by the anticodon-codon interaction in the protein biosynthesis in the ribosome.

Hydrogen-Ion Concentration↗
PubMed2005

Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA) to identify the minimum regions of maximum significance (MRMS) across populations.

In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA). Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6-7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS). Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin) at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p < 0.0001 for 160-167 cM, including D1), chromosome 3 (p-value < 0.0000001 for 287-294 cM, including D2), chromosome 5 (p-value < 0.001 for 0-7 cM, including D3), and chromosome 9 (p-value < 0.05 for 7-14 cM, the region adjacent to D4). This GSMA analysis approach demonstrates the power of linkage meta-analysis to detect multiple genes simultaneously for a complex disorder. The MRMS method enhances this powerful tool to focus on more localized regions of linkage.

Chromosomes, Human↗