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Each genome-wide run of Stubb produces, for each starting position of the sliding window, a score that measures the likelihood of the sequence having a cluster of binding sites. The next step is to extract the coordinates of each window that scores better than all other windows overlapping it. Such windows correspond to local "peaks" in the score profile along the genome. All such "peak" windows with scores above a certain threshold are sorted in decreasing order of their score, to produce a sorted list of predicted CRM's. Each window in this list is annotated with useful information including the identity and relative location of its neighboring genes. The list is then filtered to retain only those predicted CRM's where Stubb predicts occurrences of at least two weight matrices. This is a heuristic that incorporates the combinatorial nature of CRM's, i.e., their tendency to have sites for multiple transcription factors (activators as well as repressors.) Finally, any predicted CRM that overlaps with an exon is removed from the list before evaluation. The predictions made by STUBBMS and STUBBSS are listed in the files "Predicted CRM's – two species" ( Additional File 4 ) and "Predicted CRM's – single species" ( Additional File 5 ), respectively.
|
15357878_p35
|
15357878
|
Stubb runs
| 4.296199 |
biomedical
|
Study
|
[
0.9995416402816772,
0.00022366995108313859,
0.00023469219740945846
] |
[
0.9976608753204346,
0.0013086531544104218,
0.0009245258406735957,
0.00010595036292215809
] |
en
| 0.999997 |
The 792 genes which the BDGP expression database lists as showing expression during blastoderm (embryonic stages 4–6) were visually inspected. From this list, we removed genes with ubiquitous expression (426; this also removes the presumably very small number of genes whose ubiquitous expression is controlled by separate "regional" modules), extremely faint or irreproducible expression (31), or expression in pole cells or yolk nuclei only (64), as well as genes whose expression is modulated along the dv axis only (13). The remaining 258 genes show patterned expression in the somatic portion along the ap axis of the blastoderm embryo; 28 known segmentation genes not captured in the BDGP expression database were added to the list, for a total of 286 genes showing ap patterned blastoderm expression. These genes were further categorized by expression level (strong, intermediate, weak) and type of pattern (ap, ap+dv, dv+ap). ap includes gap, pair rule and segment polarity-like patterns (e.g., Kr , fkh , eve ); ap+dv denotes ap pattern with some dv modulation (e.g., kni , so , en ); dv+ap denotes dv pattern with some ap modulation (e.g., neur ).
|
15357878_p36
|
15357878
|
Annotation of gene expression database
| 4.182341 |
biomedical
|
Study
|
[
0.9993547797203064,
0.00031186130945570767,
0.0003332910710014403
] |
[
0.9989194869995117,
0.0003010577929671854,
0.0007185651920735836,
0.000060919977840967476
] |
en
| 0.999996 |
SS and EDS worked out the details of genome-wide Stubb runs. SS performed the Stubb runs, collected all statistics from the runs, and drafted the manuscript. EDS suggested several analyses reported. MDS, UU, and UG annotated the genes for expression pattern, suggested many of the analyses in the Results and Discussion sections, and wrote parts of the manuscript. All authors read and approved the final manuscript.
|
15357878_p37
|
15357878
|
Authors' contributions
| 0.825798 |
other
|
Other
|
[
0.4587445855140686,
0.005214640870690346,
0.5360407829284668
] |
[
0.012807220220565796,
0.983214259147644,
0.002702784724533558,
0.001275717979297042
] |
en
| 0.999995 |
A recently published paper also evaluates the effect of cross-species comparison on CRM prediction in Drosophila.
|
15357878_p38
|
15357878
|
Note added in proof
| 2.578074 |
biomedical
|
Study
|
[
0.9931852221488953,
0.0006293033366091549,
0.00618550693616271
] |
[
0.9233741760253906,
0.06340890377759933,
0.012250103987753391,
0.0009667593985795975
] |
en
| 0.999995 |
Mastitis is a common problem for breastfeeding women . Before planning a trial to reduce the number of lactating women who develop mastitis, we reviewed the literature to identify factors that may be associated with mastitis and to examine previous trials. A relatively small number of trials was identified which included mastitis as one of the outcome measures (see Table) . Using historical controls, prophylactic topical penicillin ointment was found to be ineffective , while hand disinfectant at the mother's bedside appeared to reduce mastitis . A Finnish study examined "breast massage" (which appears to be a variation of "nipple toughening") and found no impact of this practice on mastitis .
|
15369597_p0
|
15369597
|
Background
| 3.854844 |
biomedical
|
Review
|
[
0.9979315996170044,
0.001182433683425188,
0.0008859224617481232
] |
[
0.25764650106430054,
0.00309967459179461,
0.7385302186012268,
0.0007236498058773577
] |
en
| 0.999997 |
The authors of one trial were convinced that their intervention was effective, despite methodological difficulties . Livingstone and Stringer conducted a randomised trial for women with cracked nipples with positive cultures for Staphylococcus aureus ( S. aureus) , in Canada. They compared topical antibiotics, oral antibiotics and "optimal breastfeeding advice" and found better improvement in nipple healing in the women given oral antibiotics. In addition, they found 16 women out of 65 (25%) given non-systemic treatment developed mastitis within 7 days, compared to 1 of 19 women (5%) given systemic antibiotics (chi-square, p = 0.065) [not 0.005 as stated in their abstract]. The authors have concluded that cracked nipples colonized with S. aureus should be "treated aggressively with systemic antibiotics". However, the chi-square test used by the authors is inappropriate because one cell contains an expected value less than 5. Using Fisher's exact test, the p value is 0.10 .
|
15369597_p1
|
15369597
|
Background
| 4.043241 |
biomedical
|
Study
|
[
0.9981170892715454,
0.0016375191044062376,
0.00024543667677789927
] |
[
0.9849826693534851,
0.0033009969629347324,
0.011263147927820683,
0.00045307815889827907
] |
en
| 0.999997 |
As the Livingstone and Stringer trial had been published in a major lactation journal and was likely to be very influential in practice , it needs to be replicated in a more rigorous manner in order to assess the usefulness and safety of the intervention. Our intention was to replicate that study with an adequate sample size, rigorous definitions of nipple damage and mastitis, and double blinding of the intervention.
|
15369597_p2
|
15369597
|
Background
| 3.635837 |
biomedical
|
Study
|
[
0.9974594712257385,
0.0018392553320154548,
0.0007013102294877172
] |
[
0.9889802932739258,
0.009798448532819748,
0.0009921264136210084,
0.00022920628543943167
] |
en
| 0.999998 |
The aim of our study was to prevent mastitis in breastfeeding women with cracked nipples colonized with S. aureus . A randomised controlled trial was conducted: participating women were randomized to receive a seven day course of either an oral antibiotic (flucloxacillin) or identical placebo capsules. A follow-up visit was arranged one week after recruitment for women with positive nipple culture for S. aureus . Women with negative nipple culture were followed up by telephone at one week. All women received a final telephone interview at six weeks.
|
15369597_p3
|
15369597
|
Methods
| 3.936042 |
biomedical
|
Other
|
[
0.6026074290275574,
0.39248162508010864,
0.004910951480269432
] |
[
0.2617262005805969,
0.7155506014823914,
0.0033695134334266186,
0.01935371197760105
] |
en
| 0.999996 |
The primary outcome was the incidence of mastitis in each group in the week following recruitment. In the study by Livingstone and Stringer 30% of women with S. aureus -colonized cracked nipples who received only breastfeeding advice developed mastitis within one week. In order to detect a 50% decrease in incidence, ie mastitis occurring in 15% of women receiving oral antibiotics, a sample size of 133 women in each group is required, with 95% confidence and 80% power. Sample size was calculated using Epi-Info 6.
|
15369597_p4
|
15369597
|
Methods
| 4.062876 |
biomedical
|
Study
|
[
0.9933049082756042,
0.006255017593502998,
0.0004399832396302372
] |
[
0.9914504885673523,
0.007725095376372337,
0.00041046159458346665,
0.00041395219159312546
] |
en
| 0.999998 |
A previous study in Australia found that 62% (13/21) of cultures from breastfeeding women with cracked nipples were positive for S. aureus . An earlier study by Livingstone and colleagues found that 54% of cracked nipples of mothers with infants younger than one month were positive for S. aureus (27/50) . Assuming that 50% of cracked nipples are positive for S. aureus , we would need 133 × 2 × 2 = 532 women with cracked nipples, to recruit two groups of 133 women with S. aureus -colonized cracked nipples. To allow for loss to follow-up, it was planned to recruit 570 women.
|
15369597_p5
|
15369597
|
Methods
| 3.85158 |
biomedical
|
Study
|
[
0.9981077909469604,
0.0013962675584480166,
0.0004959669895470142
] |
[
0.9965991377830505,
0.003091919468715787,
0.00016160347149707377,
0.00014741257473360747
] |
en
| 0.999997 |
A review of the literature on the topic of nipple damage found a lack of consistency in assessment of nipple damage . Many reports have not provided a clear description of the assessment process. Some of the more recent studies have provided a more detailed description, such as Brent et al's Nipple Attribute Score and Duffy et al's Nipple Trauma Index . The Nipple Trauma Index used by Duffy and colleagues in Western Australia appeared to be useful, however a request for more information about this instrument was not successful .
|
15369597_p6
|
15369597
|
Methods
| 2.923154 |
biomedical
|
Review
|
[
0.9719887375831604,
0.006856256630271673,
0.021154969930648804
] |
[
0.006184501573443413,
0.009083539247512817,
0.9839260578155518,
0.0008059121901169419
] |
en
| 0.999997 |
Our definitions of nipple damage are as follows: mild 1 or 2 mm wide; moderate 3–9 mm wide; severe: greater than 10 mm wide and / or yellow colour visible in crack. In addition to a clinical assessment, a more permanent record of nipple damage was created using digital photography. It was planned for the photographs to be reviewed independently by three lactation consultants, in order to allow a thorough assessment of nipple damage and changes over time, rather than relying on the clinical assessment alone. (As the trial ended prematurely, this did not take place).
|
15369597_p7
|
15369597
|
Methods
| 3.092521 |
biomedical
|
Study
|
[
0.557526707649231,
0.4384433925151825,
0.004029878415167332
] |
[
0.5715692639350891,
0.4096684455871582,
0.002241980517283082,
0.01652027852833271
] |
en
| 0.999996 |
Furthermore, although the WHO defines mastitis as an inflammation of the breast , there is no generally agreed definition of mastitis for research purposes. The definition of mastitis used for this study was that a woman reported:
|
15369597_p8
|
15369597
|
Methods
| 2.063042 |
biomedical
|
Study
|
[
0.9933504462242126,
0.002590943593531847,
0.004058646038174629
] |
[
0.8535507321357727,
0.14187783002853394,
0.0026382924988865852,
0.0019331756047904491
] |
en
| 0.999996 |
• at least two breast symptoms (pain, redness, lump) and
|
15369597_p9
|
15369597
|
Methods
| 1.707005 |
biomedical
|
Other
|
[
0.8038754463195801,
0.1807837188243866,
0.015340840443968773
] |
[
0.006896269042044878,
0.9819524884223938,
0.001957956235855818,
0.009193209931254387
] |
en
| 0.999995 |
• at least one of fever or 'flu-like symptoms.
|
15369597_p10
|
15369597
|
Methods
| 1.557364 |
biomedical
|
Other
|
[
0.7210981845855713,
0.2216620296239853,
0.05723976716399193
] |
[
0.002598143182694912,
0.9896572232246399,
0.0017678033327683806,
0.005976843647658825
] |
en
| 0.857141 |
As we intended to recruit over 500 women we planned a multi-centred trial, involving a number of public and private maternity hospitals in inner Melbourne. All hospitals provide a breastfeeding clinic staffed with International Board Certified Lactation Consultants for women having breastfeeding difficulties following hospital discharge. The public hospitals, where women tend to have shorter hospital stays, also provide home visits by domiciliary midwives post discharge. It was foreseen that there would be replication in the requirements of the hospital ethics committees and logistical difficulties for one researcher (LA) to conduct the study on multiple sites.
|
15369597_p11
|
15369597
|
Multi-centred trial
| 2.141926 |
biomedical
|
Study
|
[
0.6301947832107544,
0.3554391860961914,
0.014366021379828453
] |
[
0.629114031791687,
0.3598056435585022,
0.001362195354886353,
0.009718132205307484
] |
en
| 0.999995 |
Each hospital had its own research ethics committee (or committees) and different forms to submit (at the time of this study). Approval was obtained from the Ethics Committees at La Trobe University , Royal Women's Hospital , Mercy Hospital for Women , Frances Perry House , Freemasons Maternity Hospital and Cabrini Private Hospital (24/04/02). One private hospital did not appear to have a procedure in place to deal with a research proposal. Negotiations continued with this hospital from late 2000 until mid-2002 when the hospital insisted that we sign a Sponsor Indemnity Form, which the university advised us against.
|
15369597_p12
|
15369597
|
Multi-centred trial
| 1.249052 |
other
|
Other
|
[
0.15429556369781494,
0.005039600655436516,
0.840664803981781
] |
[
0.015063184313476086,
0.9839169383049011,
0.00046874734107404947,
0.0005511969793587923
] |
en
| 0.999998 |
The researcher visited the postnatal wards and breastfeeding clinics of these hospitals each day or second day and asked a senior member of the nursing staff if there were any breastfeeding women with damaged nipples in the ward. The staff member introduced the researcher to the woman in order to inform the woman about the study and invite her to participate in the trial. Also, the researcher asked the domiciliary midwives to inform women at home with a cracked nipple about the trial. If the woman were interested in the study, the midwife gave the researcher the woman's name and phone number. After a telephone discussion, the researcher would visit her at home to assess her eligibility.
|
15369597_p13
|
15369597
|
Multi-centred trial
| 2.474147 |
clinical
|
Study
|
[
0.3084372282028198,
0.686586320400238,
0.004976453725248575
] |
[
0.5281376838684082,
0.4399479627609253,
0.002412953646853566,
0.02950143814086914
] |
en
| 0.999997 |
Thus, the researcher was visiting a number of hospitals on a daily basis and making home visits to potential participants and follow-up visits to participants one week after recruitment. Therefore, if the researcher was going to be unavailable one week, she could not recruit women the week prior (as she would not be able to follow them up).
|
15369597_p14
|
15369597
|
Multi-centred trial
| 1.914186 |
biomedical
|
Study
|
[
0.9496452808380127,
0.006956856232136488,
0.04339780658483505
] |
[
0.8116781115531921,
0.18640916049480438,
0.0006066906498745084,
0.001306018210016191
] |
en
| 0.999997 |
All potential participants had a specimen collected from their nipple crack for culture and sensitivity. As this was collected for the purpose of research rather than clinical practice, it was necessary to seek funding for the cost of the microbiological assessment. We intended to recruit 570 women, therefore substantial funds were required. A number of applications (seven) were submitted to local, national and international funding bodies in 2001. A funding application to the Medical Research Foundation for Women and Babies for 2002 was successful (A$15,000).
|
15369597_p15
|
15369597
|
Funding
| 1.900495 |
biomedical
|
Study
|
[
0.9393619298934937,
0.033153682947158813,
0.027484474703669548
] |
[
0.5857977867126465,
0.4099653363227844,
0.0008244312484748662,
0.0034123884979635477
] |
en
| 0.999999 |
We recognized that there would be a delay between recruitment (when the initial data and nipple specimen were collected) and randomization (when the result was available). The Microbiology laboratory faxed the result to the researcher (or the researcher contacted the laboratory on weekends). However, the minimum time was 2 days for the laboratory to identify S. aureus and up to 6 days in one instance (mean 3.6).
|
15369597_p16
|
15369597
|
Delay between recruitment and randomization
| 2.682604 |
biomedical
|
Study
|
[
0.846852719783783,
0.15014348924160004,
0.003003801219165325
] |
[
0.8558024168014526,
0.1353810876607895,
0.0009135394939221442,
0.007902832701802254
] |
en
| 0.999996 |
The delay meant that women would be at home when the results were available and the researcher was required to visit the participant at her home to deliver the capsules. In addition to the inconvenience, a small number of women had already developed mastitis by the time the researcher contacted her with the result.
|
15369597_p17
|
15369597
|
Delay between recruitment and randomization
| 1.768646 |
biomedical
|
Study
|
[
0.8904759287834167,
0.09607163816690445,
0.013452492654323578
] |
[
0.6172394752502441,
0.36756661534309387,
0.0016634977655485272,
0.013530430383980274
] |
en
| 0.999998 |
It was expected that a local company specializing in the preparation of placebos for drug trials would prepare the identical capsules. A common practice is to cover the active capsule with a larger capsule; participants are unaware if their capsule contains the active capsule or an inert substance. However, when the company realized that the active capsule contained a penicillin-like drug they were unable to participate, as they do not have a license for penicillin. Finally, the pharmaceutical company, CSL Ltd, provided us with identical empty capsules as well as active flucloxacillin capsules. A pharmacy technician at the pharmacy department at the Royal Women's Hospital opened each capsule manually and inserted glucose powder. Randomisation was conducted in blocks of ten, stratified according to hospital. Ten bottles were prepared for each hospital prior to the trial commencing (further capsules were not needed).
|
15369597_p18
|
15369597
|
Production of placebo capsules
| 3.10934 |
clinical
|
Other
|
[
0.388446569442749,
0.6060960292816162,
0.005457374732941389
] |
[
0.23222383856773376,
0.744561493396759,
0.0016724290326237679,
0.021542247384786606
] |
en
| 0.999997 |
Not all the women who were eligible for the trial were interested in taking part . Some women expressed a reluctance to take antibiotics, others were overwhelmed with the difficulties they were experiencing and preferred not to participate in a trial. The researchers had previously conducted studies involving breastfeeding women which had high rates of participation and had expected women to be more interested in taking part in a trial that aimed to prevent mastitis. We should have expected a lower participation rate as this study involved the possibility of taking a medication, in particular an antibiotic.
|
15369597_p19
|
15369597
|
Participation
| 2.229979 |
biomedical
|
Study
|
[
0.967177152633667,
0.028057590126991272,
0.0047651841305196285
] |
[
0.944711446762085,
0.05265317112207413,
0.0007254629163071513,
0.0019099232740700245
] |
en
| 0.999997 |
A total of approximately 17,000 women give birth in these hospitals each year. We estimated that 80% of women start breastfeeding, 5% develop cracked nipple(s), 80% would be eligible and 95% would agree to participate, thus there would be 537 eligible women per year. We anticipated that we would recruit approximately ten women with cracked nipples per week. It would therefore take 57 weeks (57 × 10) to recruit the total sample.
|
15369597_p20
|
15369597
|
Less than anticipated incidence of cracked nipples
| 2.276743 |
biomedical
|
Study
|
[
0.9756205677986145,
0.018043095245957375,
0.006336326245218515
] |
[
0.9593956470489502,
0.03940221667289734,
0.00024820593534968793,
0.0009539719903841615
] |
en
| 0.999995 |
However, recruitment was slow, as very few women were identified with damaged nipples. Hospital staff made unsolicited remarks that nipple damage was seen much less frequently than in the past. Midwives have been trained to help women position the baby and attach the baby at the breast; women are reporting the presence of nipple pain and any nipple damage is usually identified at an early stage. In the past, women may have continued to breastfeed with poor attachment of the baby to the breast, resulting in more severe damage, whereas at the time of the study maternity staff were likely to suggest "resting" the damaged nipple and expressing the milk by hand or electric pump until the damage had healed.
|
15369597_p21
|
15369597
|
Less than anticipated incidence of cracked nipples
| 2.586571 |
biomedical
|
Study
|
[
0.9245256781578064,
0.07103335112333298,
0.004440993070602417
] |
[
0.8815563321113586,
0.11218950152397156,
0.001121298992075026,
0.0051328931003808975
] |
en
| 0.999998 |
Recruitment began at two hospitals in November 2001, two others in February 2002 and a fifth hospital in June 2002. Recruitment was slow as few women had damaged nipples. During the months of the trial, the rate of recruitment decreased rather than increased. Additionally, the flucloxacillin supplied by CSL were labeled to use before the end of November 2002. Therefore it was decided to stop recruiting, once a twelve-month recruiting period had elapsed. The trial stopped recruiting on the 14 th November 2002.
|
15369597_p22
|
15369597
|
Results
| 1.846434 |
clinical
|
Other
|
[
0.28885892033576965,
0.6856923699378967,
0.025448743253946304
] |
[
0.14184339344501495,
0.8404834270477295,
0.0014016969362273812,
0.01627155765891075
] |
en
| 0.999997 |
Of the 158 women referred to the study as possible participants, 48 women were eligible (ie they had a cracked nipple, were not allergic to penicillin, did not have concurrent "nipple thrush" and had adequate English). Twenty-six of these women refused (10 not interested, 9 didn't want to take antibiotics, 7 other reason given). Therefore, 22 were potentially eligible in that they had at least one cracked nipple and consented to take part in the trial if the results of the nipple swab confirmed S. aureus . Thirteen of the nipple cultures were positive and ten women were randomized to receive flucloxacillin (n = 5) or placebo capsules (n = 5). Two women had already developed mastitis prior to receiving the results and the third woman had developed a rash and did not want to take the capsules. All women were followed-up at one week and six weeks. Of the ten women in the RCT, one woman in the placebo group developed mastitis (not in the first week of the trial, baby was 32 days old, 28 days after randomization). Three women reported that they had not taken the capsules. When the study was unblinded it showed that all three were in the placebo group.
|
15369597_p23
|
15369597
|
Results
| 3.957018 |
clinical
|
Other
|
[
0.30659398436546326,
0.6859022378921509,
0.007503771688789129
] |
[
0.13692229986190796,
0.8164883852005005,
0.00582484295591712,
0.04076454043388367
] |
en
| 0.999996 |
This trial experienced a number of problems, both foreseen and unforeseen. In the trial conducted by Livingstone and Stringer, there is no mention of women refusing to participate in the study or not taking the treatment they were allocated . It is not reported if any woman developed mastitis in the period between collection of the swab, the clinician receiving the result and the woman being given her allocated treatment regime – indeed the paper does not state that women had to return to the breastfeeding clinic for this. Possibly, women attending a breastfeeding clinic are more likely to comply with treatment regimes than women who are invited to participate in a trial.
|
15369597_p24
|
15369597
|
Discussion
| 2.647264 |
biomedical
|
Other
|
[
0.6164531111717224,
0.3768478333950043,
0.006698963697999716
] |
[
0.437619149684906,
0.5472838282585144,
0.002981549361720681,
0.012115470133721828
] |
en
| 0.999997 |
We thought the estimate of 5% of breastfeeding women developing a cracked nipple was a conservative estimate. For example, in Western Australia, Duffy et al had found that 6% of women in their intervention group had cracked nipples, compared to 69% in their control group . However, on visiting the postnatal wards and breastfeeding clinics in inner Melbourne, it was not unusual to find that the staff were unable to identify any women with damaged nipples. And of the women who were assessed, more than half did not have a cracked nipple. Therefore, nipple damage appears to be uncommon in breastfeeding women in Melbourne.
|
15369597_p25
|
15369597
|
Discussion
| 2.900362 |
biomedical
|
Study
|
[
0.9926990866661072,
0.005067493766546249,
0.0022334556560963392
] |
[
0.9918999671936035,
0.007320122793316841,
0.0003692447207868099,
0.0004106024862267077
] |
en
| 0.999997 |
In retrospect, we should have conducted a pilot or feasibility study before commencing the trial. The appropriate use of antibiotics for breastfeeding women with cracked nipples still needs to be tested. We hope our experience will be useful for others planning trials of mastitis or nipple damage.
|
15369597_p26
|
15369597
|
Conclusions
| 2.065046 |
biomedical
|
Other
|
[
0.9558512568473816,
0.03455536812543869,
0.009593388065695763
] |
[
0.1364651471376419,
0.8589407801628113,
0.001433445024304092,
0.0031605835538357496
] |
en
| 0.999996 |
None declared.
|
15369597_p27
|
15369597
|
Competing interests
| 0.828596 |
other
|
Other
|
[
0.19056588411331177,
0.00526782963424921,
0.804166316986084
] |
[
0.017649328336119652,
0.97890704870224,
0.0020668187644332647,
0.0013767849886789918
] |
it
| 0.999994 |
All authors contributed to the design of the trial, LA reviewed the literature, conducted the trial, and wrote the first draft of the paper. All authors approved the final draft of the paper.
|
15369597_p28
|
15369597
|
Authors' contributions
| 1.002795 |
other
|
Other
|
[
0.05373116582632065,
0.0031335214152932167,
0.9431352615356445
] |
[
0.0026908533181995153,
0.9960731267929077,
0.0008282405906356871,
0.0004077197809237987
] |
en
| 0.999997 |
The pre-publication history for this paper can be accessed here:
|
15369597_p29
|
15369597
|
Pre-publication history
| 1.031347 |
other
|
Other
|
[
0.013091341592371464,
0.0014214670518413186,
0.9854872226715088
] |
[
0.0015875872923061252,
0.997281551361084,
0.0006836647517047822,
0.0004471398133318871
] |
en
| 0.999997 |
Most X chromosomal genes are essential or relevant to both sexes. To cope with the difference in the number of copies of these genes in females (XX) and males (XY), organisms have evolved a variety of mechanisms, collectively termed dosage compensation, to equalize the levels of X-linked gene products in the two sexes. In Drosophila males the expression of most of the genes on the single X chromosome is doubled. At least six protein-coding genes, collectively referred to as male specific lethal s ( msl s), are required for dosage compensation : msl-1, msl-2, and msl-3, whose functions remain unknown; maleless (mle), encoding an RNA helicase; males absent on the first (mof), encoding a histone acetyltransferase; and jil-1, encoding a histone kinase. The products of these genes, together with noncoding RNAs encoded by the RNA on the X genes (roX1 and roX2) , are all reproducibly associated with hundreds of locations along the length of the polytenized salivary gland X chromosome in males. MOF has been shown both in vivo and in vitro to acetylate H4Lys16, a specific histone modification also found at sites where compensasomes are associated with the male X . Recently, JIL-1, which phosphorylates H3Ser10, was shown to be enriched at the MSL binding sites in males . Thus, MSL proteins and roX RNAs are thought to function in a ribonucleoprotein complex (compensasome) to mediate dosage compensation by altering chromatin structure of the male X chromosome . In females translational repression of msl-2 mRNA by the Sex-lethal protein (SXL) prevents formation of compensasomes and hence dosage compensation .
|
15502872_p0
|
15502872
|
Introduction
| 4.853448 |
biomedical
|
Study
|
[
0.9987207055091858,
0.0006942389882169664,
0.0005849923472851515
] |
[
0.9908252358436584,
0.0023030159063637257,
0.0063535417430102825,
0.0005182144232094288
] |
en
| 0.999995 |
The processes and constraints that generate the observed distribution of compensasomes along the male X chromosome are unknown. Although the hundreds of places where compensasomes are found along the X chromosome are referred to as “sites,” they are in fact not points, but rather bands (small segments of chromosome) that roughly span the size range of salivary chromosome bands seen with DNA stains (i.e., a few tens to several hundreds of kilobases in length). Thus, both the locations and the extents of these sites are somehow specified. Furthermore, the compensasome bands do not correspond to the bands where DNA is condensed . In addition, non-dosage-compensated X-linked genes (e.g., LSP1-α ) are scattered throughout the X chromosome and can reside next to dosage-compensated genes . Since there is no known DNA-binding component in the compensasome, and consensus DNA sequences required for binding have not yet been identified, an understanding of the distribution of compensasomes along the X chromosome needs to encompass not only how complexes are targeted to these several hundred sites, but also how the ends of each band are delimited.
|
15502872_p1
|
15502872
|
Introduction
| 4.440736 |
biomedical
|
Study
|
[
0.9992920160293579,
0.0002790363796520978,
0.0004290118522476405
] |
[
0.9963282942771912,
0.0014243018813431263,
0.00212022103369236,
0.00012721592793241143
] |
en
| 0.999998 |
A proposal for how the distribution of compensasome bands along the X chromosome is generated has come from the following findings. MSL-1 and MSL-2 represent core components of the complex: The presence of both is required for either to bind, and none of the other MSL proteins binds to the X chromosome in an msl-1 or msl-2 mutant male . Furthermore, in males mutant for mle, msl-3, or mof, binding of MSL-1 and MSL-2 is only maintained at a limited number of sites (35–40) on the X chromosome, which include the roX1 and roX2 genes . Finally, roX transgenes inserted into an autosome retain binding of compensasomes, and in addition show compensasome binding in the autosomal region flanking the insertion site, a phenomenon termed spreading . Based on these observations, a reasonable model emerged suggesting that the 35–40 sites of MSL-1 and MSL-2 binding on the X seen in mle, msl-3, or mof mutants represent nucleation sites or entry sites for the complex. From these sites, newly assembled compensasomes would spread in cis along the X to form the hundreds of final sites observed in a wild-type male. In this spreading model, roX RNAs would also be required for compensasome assembly . However, there is to date no direct evidence that entry sites and spreading play any role in the processes that generate the normal pattern of compensasome binding along the X chromosome. We thus directly tested this model by analyzing various pieces of the X chromosome transposed or translocated to autosomal locations for their ability to bind compensasomes and initiate spreading.
|
15502872_p2
|
15502872
|
Introduction
| 4.476751 |
biomedical
|
Study
|
[
0.9990418553352356,
0.0005513056530617177,
0.0004068782727699727
] |
[
0.9988834261894226,
0.0004861870256718248,
0.0004924810491502285,
0.00013792584650218487
] |
en
| 0.999998 |
The spreading model implies that a piece of the X chromosome translocated to an autosome must contain at least one of the 35–40 “entry” sites if that piece of the X is to recruit compensasomes and become dosage compensated. We looked at MSL binding in various chromosome rearrangements that inserted small pieces of X chromosome into autosomal locations. Table 1 summarizes the translocations, transpositions, and duplications examined. The insertions in the first set (lines I to XI) range in size from about 1% to 15% of the length of the X, and the corresponding stretch of X chromosome for each contains 1–19 distinguishable MSL bands. These insertions were examined in heterozygous condition so we could readily identify the junctions between X chromosomal and autosomal material. When large enough, they appear as a loop of unpaired chromosome protruding from the paired autosomes. We found that transpositions containing one (lines VI to VIII) or several (lines I to V) previously described entry sites showed consistent MSL binding along the inserted piece . Surprisingly, transposed pieces of X chromosome lacking any entry site also showed MSL binding when inserted into an autosome . For all of these 11 transpositions the binding pattern observed and the intensity of MSL bands reproducibly matched the expected pattern of that piece of the X chromosome in a wild-type male. Even the smallest piece we looked at (line X, approximately 200 kb) showed one to two MSL bands . Thus, we found that any piece of the X chromosome moved to an autosomal location is able to bind compensasomes, whether or not the transposed piece of X chromosome contains an entry site. This finding suggests that each of the hundreds of MSL bands observed on the X in males carries the information necessary and sufficient to attract compensasomes, and does not require adjacent entry sites.
|
15502872_p3
|
15502872
|
Results
| 4.460646 |
biomedical
|
Study
|
[
0.9992380142211914,
0.00046743539860472083,
0.00029453547904267907
] |
[
0.9989659786224365,
0.000444328150479123,
0.00045227017835713923,
0.00013743578165303916
] |
en
| 0.999997 |
Interestingly, duplications showed binding both along the autosomal insertion and on the X chromosome (lines II and XI), indicating that the supply of compensasomes is not limiting in these circumstances. We also tested homozygous transpositions and duplications for MSL binding in males and found that we could recover MSL binding on each homozygous transposed piece (unpublished data) as well as on the X. Thus, even three copies of the same segment of the X chromosome (two of the duplication plus the original piece on the X) were able to maintain MSL binding. This result extends previous data showing that, by using specific msl-2 transgenes escaping SXL repression, ectopic expression of MSL-2 in females induced binding to both X chromosomes, in a pattern identical to the single X of a wild-type male . Therefore, binding occurs regardless of the location and number of copies of the X-linked targeted sequences.
|
15502872_p4
|
15502872
|
Results
| 4.176098 |
biomedical
|
Study
|
[
0.9994198083877563,
0.0002701419871300459,
0.0003101115289609879
] |
[
0.9994244575500488,
0.0003276392526458949,
0.00018071728118229657,
0.00006714720802847296
] |
en
| 0.999996 |
The determinations listed in Table 1 of how many entry sites each of the transpositions contains were made by comparing the reported breakpoints of each rearrangement to the described locations of entry sites . As cytological determinations can vary, we directly confirmed the presence or absence of entry sites by examining MSL binding in an msl-3 or mle mutant background for a subset of these transpositions . Each line used in these experiments contained the transposed region from the X inserted into an autosome and a wild-type X chromosome. For line XI we found that, in mle mutant individuals, MSL binding was undetectable in either the transposed region (3A5–E8) inserted at 87E17 or in this region in the wild-type X. As expected, the same is true when only a subset of this region is duplicated: Line X did not show binding in mle mutants to region 3C2–3C6 on the X or to the transposition of that region inserted at 61D . These findings confirm that lines X and XI do not contain entry sites. Similarly, we confirmed that transpositions inferred to contain entry sites in two lines (IV and VI) did in fact contain such sites. Thus, for line IV in an mle mutant background we observed MSL binding to one to three sites on both the transposition and the corresponding region of the X , while for line VI in an msl-3 mutant background we observed one site of MSL binding on both the transposition and the corresponding region of the X . These findings are consistent with those of Lyman et al. , who reported two entry sites in the region encompassed by the transposition in line VI, and one entry site in the region encompassed by the transposition in line IV. Our findings firmly establish that isolated subregions of the X chromosome display normal patterns of compensasome binding irrespective of whether they contain entry sites, and thus suggest that entry sites do not play a distinct role in the establishment of compensasome binding along the X as postulated by the spreading hypothesis. Hereafter we will refer to entry sites as high-affinity sites, their original name . During the course of this study, Oh et al. have reported similar results for binding of compensasomes to transpositions from lines I, VIII, and IX. However, the scale of the analysis and the limited number of rearrangements did not yield the same conclusions.
|
15502872_p5
|
15502872
|
Results
| 4.408695 |
biomedical
|
Study
|
[
0.9993168115615845,
0.0003766680310945958,
0.00030646295635960996
] |
[
0.9990448355674744,
0.0002635103592183441,
0.0005963726434856653,
0.00009523464541416615
] |
en
| 0.999996 |
The two high-affinity sites identified to date correspond to the roX1 and roX2 genes , and it was the fact that roX transgenes inserted into autosomal locations are able to induce spreading—binding of the MSLs to some autosomal sequences surrounding a roX transgene insertion site—that led to the hypothesis that spreading gives rise to the wild-type distributions of compensasome bands along the male X chromosome. We therefore examined whether autosomal transpositions of a piece of the X were able to induce spreading. In cells heterozygous for each of the transpositions listed above we never observed additional MSL binding to the autosomal regions either cis or trans to the insertion site . We also did not observe additional MSL binding in males homozygous for the transpositions described above. This was true irrespective of the number of high-affinity sites contained in the transpositions. Interestingly, lines I and V, which each contain several high-affinity sites, including the roX1 or roX2 gene, respectively, showed no spreading in males wild-type for the MSLs . The dichotomy between our results and those obtained with roX transgenes suggests that spreading may be a phenomenon restricted to some roX transgenes (see below) and not an aspect of dosage compensation.
|
15502872_p6
|
15502872
|
Results
| 4.241364 |
biomedical
|
Study
|
[
0.9993557333946228,
0.000308415008476004,
0.0003358407411724329
] |
[
0.9993875026702881,
0.00025358746643178165,
0.0002902989217545837,
0.00006860944267828017
] |
en
| 0.999995 |
To further assess if spreading in cis occurs on the X chromosome, we next asked if the complex could spread from the X onto an autosomal piece attached to the X by a reciprocal translocation. We tested two reciprocal translocations that interchanged large portions of the X and 3R or 2L (see Table 1 , lines XII and XIII, respectively). Both translocations separate roX1 (3F) and roX2 (10C) genes from one another and thus both pieces of each translocation contain a roX locus. Anti-MSL-1 staining revealed the absence of any bands on either of the 3R or 2L pieces of these translocations , while the pattern observed on the two transposed pieces of the X was normal. These results strengthen the idea that spreading may be a phenomenon restricted to roX transgenes, since the breakpoints in line XII (10A) and line XIII (5A) are relatively close to the roX2 (10C) and roX1 (3F) loci, respectively.
|
15502872_p7
|
15502872
|
Results
| 4.210352 |
biomedical
|
Study
|
[
0.9993478655815125,
0.00029094290221109986,
0.0003612214932218194
] |
[
0.9994615912437439,
0.0002803230017889291,
0.00019917424651794136,
0.000058869842177955434
] |
en
| 0.999997 |
We also tested two small transpositions of autosomal regions into the X : Neither of them showed MSL binding, even weak, to any part of the inserted autosomal sequences. Furthermore, females either heterozygous or homozygous for these transpositions and expressing ectopic MSL-2 did not show any MSL bands in either of these insertions of autosomal material into the X, although they displayed normal MSL binding both to the unpaired X region (in heterozygotes) and along the paired portions of the two X chromosomes . Thus, insertion of a piece of an autosome into the X does not disrupt MSL binding to either the unpaired X homologue at the insertion site or the regions of the X immediately flanking the site of insertion of autosomal material. Moreover, these results are inconsistent with the model derived from the roX transgene studies where MSL binding is observed both in the autosomal regions adjacent to the insertion site and on the wild-type autosomal homologue.
|
15502872_p8
|
15502872
|
Results
| 4.223957 |
biomedical
|
Study
|
[
0.9993517994880676,
0.00028654400375671685,
0.0003617405309341848
] |
[
0.9993714690208435,
0.0003006496117450297,
0.0002653608098626137,
0.00006254835898289457
] |
en
| 0.999996 |
In summary, we have used chromosome rearrangements to test two central aspects of the proposed spreading model of dosage compensation in Drosophila. It is worth noting that our experiments were a priori neutral: They could have provided compelling evidence for or against the spreading model. In both cases our results are inconsistent with the clear predictions of that model. First, we show that pieces of the X chromosome inserted into an autosome bind compensasomes in precisely the pattern characteristic of that piece of the X at its endogenous location on the X, and this property is independent of the presence of sites previously described as entry sites. Second, compensasomes do not spread from the X into autosomal pieces inserted into, or translocated onto, the X. Moreover, there is not spreading of compensasomes from autosomal insertions of pieces of the X chromosome into the autosomal regions flanking the insertion, even when such pieces contain a roX gene close to the breakpoint. These results suggest that spreading in cis is not part of the process of dosage compensation in flies. We thus propose that all of the hundreds of sites along the X chromosome where compensasomes are found in wild-type males are competent to independently recruit compensasomes.
|
15502872_p9
|
15502872
|
Discussion
| 4.382668 |
biomedical
|
Study
|
[
0.9992828965187073,
0.0004168414161540568,
0.0003002797020599246
] |
[
0.9988545179367065,
0.00034646480344235897,
0.0006954542477615178,
0.00010345347982365638
] |
en
| 0.999995 |
Our findings raise several questions regarding previous data. Are the 35–40 sites that attract partial complexes in mle or msl-3 mutants qualitatively different from the other sites at which MSL bands are found in wild-type, and if so, how? Why do roX transgenes induce additional binding to adjacent autosomal sequences?
|
15502872_p10
|
15502872
|
Discussion
| 3.462998 |
biomedical
|
Study
|
[
0.9966439008712769,
0.0002501131093595177,
0.003106009680777788
] |
[
0.8921120166778564,
0.10405619442462921,
0.003348942380398512,
0.00048292262363247573
] |
en
| 0.999996 |
With respect to the potential heterogeneity of compensasome binding sites, while most of the relevant data are indirect (only the roX1 and roX2 genes are identified binding sites), the data are consistent with the simple view that the binding sites are homogeneous in terms of their function, but have varying affinities for compensasomes. Our finding that pieces of X chromosome transposed to autosomal locations display normal patterns of compensasome binding, irrespective of whether or not they contain high-affinity sites, removes the one functional distinction between binding sites that had been proposed. That there are not two classes of binding sites in terms of affinity for compensasomes, but rather a continuum of affinities, is strongly suggested by the recent report of Demakova et al. , who carefully characterized the number and locations of compensasome bands in mutant females expressing various limiting amounts of MSL-2. They found only four bands in the most limiting case, and progressively higher numbers of bands as more MSL-2 protein was expressed. Interestingly, the intermediate 40 sites at which complete complexes are assembled in these conditions exactly matched with the 35–40 high-affinity sites bound by partial complexes in mle or msl-3 mutants. Their data are consistent with a model in which compensasomes continue to bind site specifically to additional sites after all high-affinity sites are occupied, as opposed to spreading from high-affinity sites as previously proposed. Given these findings, a reasonable scenario as to how dosage compensation is achieved would be the following. As MSL expression begins, the high-affinity sites progressively sequester nascent partial or full complexes in the early stages of dosage compensation. When the amount of available complexes or its components increases, sites of higher affinity would accumulate more complexes, while low-affinity sites would remain undetectable, until the former have preferentially assembled sufficient amounts of complexes to make components available for sites with lower affinities. Thus, the compensasomes would progressively bind to different sites along the X according to the different affinities of these sites. Consistent with our model, we found that in mle or msl-3 mutants, duplications maintain binding of partial complexes at the high-affinity sites , though with a lower affinity than the same site on the X. The latter observation suggests that, in conditions where components of the complex are limiting, binding might also be dependent on the location of these sequences in the cell (see discussion on spreading below).
|
15502872_p11
|
15502872
|
Discussion
| 4.57318 |
biomedical
|
Study
|
[
0.9989086389541626,
0.0006108276429586112,
0.00048049684846773744
] |
[
0.9986976385116577,
0.0004915290628559887,
0.0006503397598862648,
0.00016041999333538115
] |
en
| 0.999998 |
That compensasome binding sites would have a range of affinities is also consistent with what is known about DNA-binding proteins, which recognize with varying affinities a range of binding sites whose sequences are related to a common consensus. Variations from the consensus can allow temporal and quantitative modulation of individual genes, or subsets of genes. That compensasome binding sites are also likely to vary in sequence, and hence affinities, comes from what is known about sex chromosome evolution in Drosophila species . During the course of sex chromosome evolution in this genus there are a number of cases in which new X chromosomes have evolved, and in all cases examined to date, this has been accompanied by the new X chromosome gradually acquiring compensasome binding sites as the new Y chromosome, its former homologue, degenerates. The selective advantage of dosage compensation for each gene is determined both by the state of degeneration of the allele on the new Y chromosome and by the degree to which a gene in males requires its function, and thus its expression, to match the output of both wild-type female X chromosomes . Hence, one would expect individually evolved binding sites to exhibit a range of affinities for compensasomes. Finally, we note that each of the final compensasome bands on the X chromosome displays a reproducible but specific intensity, likely to reflect not only different affinities for compensasomes, but also the length of X chromosome encompassed in each band.
|
15502872_p12
|
15502872
|
Discussion
| 4.471991 |
biomedical
|
Study
|
[
0.9992220401763916,
0.0003321718249935657,
0.00044575962238013744
] |
[
0.9984682202339172,
0.0003977817832492292,
0.0010427351808175445,
0.0000911505485419184
] |
en
| 0.999995 |
The last issue we wish to address is spreading. The fact that, in chromosome rearrangements that juxtapose pieces of X and autosome, we never observed spreading, even when entry sites or roX genes were near the breakpoints, suggests that spreading does not exist naturally on the X chromosome, and is not required to establish the final pattern of binding in Drosophila males. Yet spreading from roX transgenes is very well documented in a variety of situations. We therefore suggest that spreading is a phenomenon specific to the roX transgenes, and a consequence of the key function of roX RNAs in dosage compensation. In particular, we propose that the roX genes are the sites of assembly of compensasomes using newly synthesized roX RNAs, just as the ribosomal RNA genes are the sites where ribosomes are assembled. Thus, roX transgenes would generate a high local concentration of compensasomes in their vicinity, competing with other chromatin-binding factors that normally bind to nearby autosomal sequences. In some cases, compensasomes would displace these other factors, resulting in a new compensasome band in the autosomal region flanking the transgene (spreading). Several features of spreading are consistent with this proposal. First, additional bands corresponding to spreading from roX transgenes contain roX RNA and the H4Lys16 modification, suggesting that they correspond to mature complexes . Second, transcription from a roX transgene is required to observe spreading of the complex onto neighboring regions . Third, roX transgenes show variable and often no additional bands in a wild-type background, suggesting that spreading is largely dependent on the insertion site and its environment on the autosomes. One possibility would be that these roX transgenes lacking spreading are inserted next to sites bound by factors normally counteracting the effect of compensasomes on the autosomes. Such a view is supported by recent data showing that association of compensasomes at some roX1 transgenes can overcome the effect of methylation-mediated silencers . Finally, MSL-1 and MSL-2 co-overexpression leads to mislocalization of partial MSL complexes to the autosomes and the centromere, as well as a dramatic decompaction of the X , a male-specific phenotype also observed in both iswi or nurf mutants, two chromatin regulators . Thus, increasing locally the amount of available complexes can induce new binding of MSL complexes to usually non-dosage-compensated regions.
|
15502872_p13
|
15502872
|
Discussion
| 4.710986 |
biomedical
|
Study
|
[
0.9985895752906799,
0.0009001133148558438,
0.0005102998693473637
] |
[
0.9977008700370789,
0.000918256351724267,
0.001076654065400362,
0.0003042538301087916
] |
en
| 0.999997 |
Molecular studies of dosage compensation in flies, worms, and mammals have revealed some striking similarities between these systems. In all three systems dosage compensation is achieved by a widespread modification of the structure of X chromosome chromatin, and in mammals and flies this involves specific modifications of histones. Dosage compensation in mammals and flies is also similar in that noncoding RNAs are essential components of the dosage compensation machinery. With respect to the other components of the dosage compensation machinery the situation is less clear. While compensasome-related complexes might be present in mammals (orthologs of msl-1, -2, -3, mle, and mof genes exist in mammalian genomes), some of them have identified functions not related to dosage compensation, and orthologs of msl-1, -2, and -3 were not found in Caenorhabditis elegans . Up until now it had also been thought that spreading was involved in dosage compensation in all three systems . However, our findings indicate that in flies each of the bands on the X chromosome at which compensasomes are found in males is able to independently attract those complexes. Thus, at the interband level spreading does not appear to be part of the dosage compensation process in flies. However, it should be noted that our results do not address either how compensasomes are distributed across the tens of kilobases of DNA that likely comprise individual compensasome bands in salivary gland chromosomes, or how that distribution is achieved; it is possible that, at the level of single bands, spreading may be part of the process of dosage compensation.
|
15502872_p14
|
15502872
|
Discussion
| 4.412563 |
biomedical
|
Study
|
[
0.9993345141410828,
0.0003454356628935784,
0.00032002193620428443
] |
[
0.9981822967529297,
0.00032360415207222104,
0.001387898693792522,
0.0001061707444023341
] |
en
| 0.999997 |
Flies were raised on standard cornmeal-yeast-agar medium. Fly stocks containing transpositions were obtained from the Bloomington Drosophila Stock Center. Their genotypes are: Tp(1;2)rb + 71 g, ct 6 v 1 /C(1)DX, y 1 w 1 f 1 (line I); Df(1)ct-J4, In(1)dl-49, f 1 /C(1)DX, y 1 w 1 f 1 ; Dp(1;3)sn 13a1 /+ (line II); Tp(1;2)sn + 72d, f 1 car 1 /C(1)DX, y 1 f 1 ; Dp(?;2)bw D , bw D (line III); Tp(1;3)w vco , v 1 f 1 : in w vco /ClB, B 36d (line IV); Tp(1;3)v + 74c/FM7a (line V); Tp(1;2)w-ec, ec 64d cm 1 ct 6 sn 3 /C(1)DX, y 1 w 1 f 1 (line VI); Tp(1;3)f + 71b/FM6 (line VII); Tp(1;3)JC153, v 1 /FM7a (line VIII); Tp(1;3)sta, sta 1 : ss sta /FM3 (line IX); Tp(1;3)w zh , sc 1 z 1 w zh (line X); Df(1)w258–45, y 2 sn 3 /C(1)DX, y 1 w 1 f 1 ; Dp(1;3)w + 67k/+ (line XI); T(1;3)v, v A /FM6 (line XII); Tp(2;1)odd 1.10 , b 1 pr 1 cn 1 sca 1 /CyO (line XIII); Df(2 l)sc19–7/In(2 l)Cy L t R In(2R)Cy, Cy 1 amos Roi-1 cn 2 sp 2 or Dp(2;1)B19, y 1 ed 1 dp o2 cl 1 (line XIV); Dp(3;1)2–2, w 1118 ; Df(3R)2–2/TM3, Sb 1 (line XV). Breakpoints and insertion site are referred in Table 1 . Some lines contain additional rearrangements referenced in Lindsey and Zimm . Depending on their genotype, each line was crossed to Canton-S males or females for studies of MSL binding in their male progeny. For homozygous transpositions studies, stocks were balanced to give w; Tp(1;2)/Cyo-GFP or w; Tp(1;3)/TM3-GFP stocks. Non-GFP third instar male larvae were dissected for analysis. For autosome-to-X transpositions, females from lines XIV and XV were mated with w; msl2Δ3–21/CyoGFP or Dp(A;1)/Y; msl2Δ3–21/CyoGFP males. Non-GFP female larvae were dissected. For mle and msl-3 mutant analysis, stocks were balanced to give w; Tp(1;2)/CyoGFP; msl3 p /TM3-GFP or w; prmle 12.17 /CyoGFP; Tp(1;3)/TM3-GFP stocks. Females were crossed to w; msl3 p /CyoGFP; msl2Δ3–10/TM3-GFP or mle 1 cnbw/CyoGFP; msl2Δ3–21/TM3-GFP males, respectively. Non-GFP third instar female larvae were dissected for salivary glands polytene chromosomes analysis. Lines expressing MSL-2 from transgenes msl2Δ3–21 and msl2Δ3–10 are described in Bashaw and Baker . Mle and msl-3 mutants are described in Fukunaga et al. , Kuroda et al. , and Gorman et al. . All crosses to generate larvae for immunostaining were carried out at 18 °C.
|
15502872_p15
|
15502872
|
Fly strains and genetic crosses
| 4.141253 |
biomedical
|
Study
|
[
0.9989783763885498,
0.00022724184964317828,
0.0007944389362819493
] |
[
0.9671820402145386,
0.030877234414219856,
0.0016034177970141172,
0.00033724115928635
] |
en
| 0.999995 |
Glands from male third instar larvae were dissected in PBS/0.7% NaCl, prefixed in 45% acetic acid for 10 s, and then fixed for 2–3 min in lactic acid/water/acetic acid (1:2:3) solution on siliconized coverslips. Glands were squashed and coverslips flipped off after freezing the slides in liquid nitrogen. Slides were then incubated in PBS for 15 min followed by incubation with affinity-purified anti-MSL-1 antibodies (dilution 1:100) as described previously . Chromosomes were viewed under epifluorescence optics on a Zeiss Axiophot microscope or a confocal microscope; pictures were taken using Spot software and colored.
|
15502872_p16
|
15502872
|
Polytene chromosome immunostaining
| 4.159414 |
biomedical
|
Study
|
[
0.9994483590126038,
0.00029567157616838813,
0.0002558733685873449
] |
[
0.9816725850105286,
0.017213303595781326,
0.0007990087033249438,
0.0003151464043185115
] |
en
| 0.999998 |
Clones RP-98 17.E.2, RP-98 03.D.13, and RP-98 48.O.22 from the Drosophila melanogaster BAC library (BACPAC Resources, Oakland, California, United States) were used to map regions 3D–E, 3C, and 2D5–3A2, respectively. Specific probes were obtained from BAC clone DNA preparations using the Bionick Labelling System (Invitrogen, Carlsbad, California, United States) according to the manufacturer's instructions. Squashes were prepared as described above. Immunostaining with affinity-purified anti-MSL-1 antibodies was followed by incubation with the appropriate biotinylated probe according to the method of Lavrov et al. .
|
15502872_p17
|
15502872
|
Immunofluorescent in situ hybridization of polytene chromosomes
| 4.104927 |
biomedical
|
Study
|
[
0.9995242357254028,
0.00016415932623203844,
0.00031155889155343175
] |
[
0.9987898468971252,
0.0008861335809342563,
0.00026241273735649884,
0.00006158589530969039
] |
en
| 0.999997 |
The LocusLink ( http://www.ncbi.nlm.nih.gov/LocusLink/ ) accession numbers for the genes and gene products discussed in this paper are jil-1 , mle , mof , msl-1 , msl-2 , msl-3 , roX1 , roX2 , and SXL .
|
15502872_p18
|
15502872
|
Accession Numbers
| 1.728506 |
biomedical
|
Other
|
[
0.982100784778595,
0.0011973630171269178,
0.016701923683285713
] |
[
0.02832626737654209,
0.9701219797134399,
0.000768856261856854,
0.0007829722599126399
] |
en
| 0.999997 |
Predicting healthcare costs for pediatric populations has been challenging . Although population-based risk prediction and case-mix adjustment can be used to inform policy, set rates, and compare outcomes across providers , a more immediate concern for healthcare providers is to clinically manage their enrolled population. In a prospective payment system with predetermined funding limits, providers must be able to proactively case-manage those enrollees at greatest risk of poor health while remaining within designated budget constraints. If healthcare providers knew in advance – for example at the time of health plan enrollment – which children were at the greatest risk for future health problems, then healthcare resources could be proactively targeted to those children in order to minimize or prevent morbidity and associated healthcare costs.
|
15361252_p0
|
15361252
|
Background
| 3.653165 |
biomedical
|
Other
|
[
0.9016483426094055,
0.05046396702528,
0.04788774624466896
] |
[
0.022076930850744247,
0.972041130065918,
0.005078451707959175,
0.0008034679922275245
] |
en
| 0.999996 |
Researchers working with adult populations have linked health status with several important outcomes. In general populations, self-reported health status has been shown to be a predictor of future health services charges , the use of physician services and mortality in working-age adults , and of frailty in the elderly . For chronically ill adults, self-rated health status is an independent predictor of physiologic health in diabetes and hypertension, and self-reported quality of life is an independent predictor of survival in cancer patients . For the hospitalized elderly, functional status and depressive symptoms have been shown to be predictive of resource utilization and mortality. Several researchers have demonstrated that both diagnostic information and self-rated health status are associated with costs for general adult populations . In pediatric populations, diagnosis-based classification systems have achieved some degree of association with healthcare costs . However, there remain limitations with current pediatric healthcare cost prediction methods, including the underestimation of healthcare costs for chronically ill children . The ideal pediatric cost prediction model for clinical management would predict healthcare costs proactively in those patients at greatest risk.
|
15361252_p1
|
15361252
|
Background
| 4.031777 |
biomedical
|
Review
|
[
0.994662880897522,
0.0016069312114268541,
0.0037301902193576097
] |
[
0.051894232630729675,
0.0016823337646201253,
0.946148157119751,
0.00027537380810827017
] |
en
| 0.999997 |
Increasingly, health-related quality of life (HRQL) has become recognized as an important health outcome, some contend the most important outcome in child health services research . Researchers have made great strides in conceptualizing and measuring HRQL for children . HRQL has been shown to be responsive to treatment in children with rheumatic disease , and to be related to treatment status in children with cancer , to chronic health condition status in a general sample , to severity of illness within children with cardiac diagnoses , and to parent reports of primary care quality and barriers to care . Measuring HRQL in large populations has several distinct benefits. It can aid in identifying subgroups of children who are at-risk for health problems , in determining the burden of a particular disease or disability , and, at least in general populations, in informing efforts aimed at prevention and intervention . While self-report is considered the standard for measuring perceived HRQL as an outcome, it is typically parents' perceptions of their children's HRQL that influence healthcare utilization .
|
15361252_p2
|
15361252
|
Background
| 3.991005 |
biomedical
|
Review
|
[
0.9924505352973938,
0.0021568364463746548,
0.00539266737177968
] |
[
0.03699055314064026,
0.0016414677957072854,
0.9611402153968811,
0.00022773552336730063
] |
en
| 0.999996 |
Consequently, the objective of this study was to test the primary hypothesis that parent proxy-report of pediatric HRQL would prospectively predict pediatric healthcare costs over a two-year period. The exploratory hypothesis tested anticipated that a relatively small group of children would account for a disproportionately large percent of healthcare costs.
|
15361252_p3
|
15361252
|
Background
| 3.720304 |
biomedical
|
Study
|
[
0.9965994954109192,
0.001973382430151105,
0.0014271755935624242
] |
[
0.9989633560180664,
0.000778896443080157,
0.0001536924100946635,
0.00010399805614724755
] |
en
| 0.999999 |
The study took place in San Diego, California between January 1998 and December 2000. We recruited members of a 50,000-member federally supported (Medicaid) managed care health plan. Additional inclusion criteria were that children be between 2 and 18 years of age and that the parent be able to speak either English or Spanish. We exclude children under 2 years of age because the PedsQL™ does not assess parent proxy-report HRQOL below age 2 years. In order to maximize the heterogeneity of the sample, subjects were recruited from three types of healthcare settings: children presenting at pediatricians' offices for scheduled well-child checks (n = 18, 5.7%), children at one of two hospital specialty clinics – orthopedics (n = 6, 1.9%) and cardiology (n = 7, 2.1%) – or children who had been seen at the hospital or its outpatient clinics at least three months previously (n = 286, 90.3%). The data reported here were collected as part of the initial field test to assess the reliability and validity of the PedsQL™ 4.0 Generic Core Scales . Only pediatric patients reported being members of the federally supported managed care health plan are included in the current data analysis.
|
15361252_p4
|
15361252
|
Participants and Settings
| 3.80929 |
biomedical
|
Study
|
[
0.9975601434707642,
0.0009853708324953914,
0.0014544461155310273
] |
[
0.9995415210723877,
0.0003136401064693928,
0.00009402151772519574,
0.000050911021389765665
] |
en
| 0.999997 |
The PedsQL™ 4.0 Generic Core Scales were designed to measure the core physical, mental and social health dimensions as delineated by the World Health Organization , and to additionally include role (school) functioning. The 23-item PedsQL™ 4.0 encompasses both physical functioning (8 items) and psychosocial (emotional, social, role) functioning (15 items) and is comprised of parallel child self-report and parent proxy-report formats. The parent proxy-report form is designed to assess the parent's perceptions of their child's HRQL. Parent proxy-report includes ages 2–4 (toddler), 5–7 (young child), 8–12 (child), and 13–18 (adolescent).
|
15361252_p5
|
15361252
|
The PedsQL™ 4.0 (Pediatric Quality of Life Inventory™ 4.0) Generic Core Scales
| 3.939569 |
biomedical
|
Other
|
[
0.9948344230651855,
0.002830678131431341,
0.002334846183657646
] |
[
0.48846495151519775,
0.5046823620796204,
0.006185573525726795,
0.0006671652081422508
] |
en
| 0.999996 |
Higher PedsQL™ 4.0 scores indicate better HRQL. To create Scale Scores, the mean is computed as the sum of the items divided by the number of items answered (this accounts for missing data). If more than 50% of the items in the scale are missing, the Scale Score is not computed. Imputing the mean of the completed items in a scale when 50% or more are completed is generally the most unbiased and precise method . Because parent proxy-report of HRQL has been shown to be related to utilization , we used only the parent proxy-report Physical Functioning and Psychosocial Functioning Summary Scales of the PedsQL™ 4.0 in the current investigation.
|
15361252_p6
|
15361252
|
The PedsQL™ 4.0 (Pediatric Quality of Life Inventory™ 4.0) Generic Core Scales
| 3.918758 |
biomedical
|
Study
|
[
0.9982507824897766,
0.0006563163478858769,
0.0010928610572591424
] |
[
0.9974794983863831,
0.0022298619151115417,
0.00022822451137471944,
0.00006247706187423319
] |
en
| 0.999997 |
Parents were asked to report on the presence of a chronic health condition for their child. They read the following statement: "A chronic health condition is: (1) a physical or mental health condition (2) that has lasted or is expected to last at least 6 months and (3) interferes with your child's activities." They then responded with yes or no to the question "In the past 6 months, has your child had a chronic health condition?" If yes, the parents were asked to identify the name of the chronic health condition. Parents who answered yes or who gave the name of a chronic health condition were coded as having a child with a chronic health condition. This method has been used in previous work , and the PedsQL™ 4.0 scores for the two groups defined using this method (with and without chronic health condition) are very similar to those observed in other studies .
|
15361252_p7
|
15361252
|
Chronic health condition status
| 3.480973 |
biomedical
|
Study
|
[
0.9966104626655579,
0.0010229864856228232,
0.0023665004409849644
] |
[
0.9988081455230713,
0.0009812035132199526,
0.0001467491965740919,
0.00006397109245881438
] |
en
| 0.999999 |
Healthcare costs were calculated as the dollar amount paid by the health plan per patient. We first determined patients' eligibility from the health plan's eligibility data files for three consecutive cumulative periods: 0–6 months, 0–12 months, and 0–24 months after the date they completed the PedsQL™ 4.0. A pediatric patient was considered eligible for health plan benefits for those periods if they were eligible for at least 5 months out of the 6-month period. We then electronically captured healthcare costs (the dollar amount paid by the health plan) for each pediatric patient for those periods in which they were eligible. We did this by matching each eligible pediatric patient with the health plan's existing databse of claims and encounter data. These data include the dollar amount spent by the health plan. Healthcare costs included hospital and emergency room costs, professional fees, durable medical equipment, home health, specialty clinic, and primary care costs. We did not have access to pharmacy or mental health costs.
|
15361252_p8
|
15361252
|
Healthcare Costs
| 3.805659 |
biomedical
|
Study
|
[
0.9847299456596375,
0.012550774030387402,
0.002719306154176593
] |
[
0.9960067868232727,
0.0034226926509290934,
0.00030732492450624704,
0.00026330651598982513
] |
en
| 0.999997 |
In California, the site of the study, treatment for 22 specific diagnoses is "carved out," or paid through a separate program (called California Children's Services; CCS) regardless of a child's health plan membership. Thus, for health plans in California, treatment of CCS-covered diagnoses might not be measured in calculating utilization. However, because California's carve out may differ from other states' methods of financing treatment for these diagnoses, and to more completely describe healthcare costs, we included the costs for procedures covered by CCS in our healthcare costs calculations. To derive these costs, we linked the procedure codes on the health plan's CCS referral with the federally supported health plan's fee schedule. These data thus represent the dollar amount the health plan would have spent had the services not been carved out.
|
15361252_p9
|
15361252
|
Healthcare Costs
| 2.229909 |
biomedical
|
Study
|
[
0.5912445783615112,
0.007286590989679098,
0.40146878361701965
] |
[
0.8250309824943542,
0.17371690273284912,
0.0005623920587822795,
0.0006897497805766761
] |
en
| 0.999997 |
A convenience sample – subects were recruited nonsystematically when research assistants were available – was recruited at pediatrician offices and specialty clinics. These pediatric patients were identified through examination of the clinic appointment schedules. At these sites, parents of children identified as possible study participants were informed of the study by one of the research assistants after checking in for their appointment, but before being seen by their healthcare provider. Written informed consent included permission for the researchers to examine the medical record to assess utilization. After written informed consent was obtained, the parent completed the proxy-report version of the PedsQL™ 4.0. The research assistant was available at all times to answer any questions.
|
15361252_p10
|
15361252
|
Procedure
| 2.537996 |
biomedical
|
Study
|
[
0.9899763464927673,
0.005696531850844622,
0.0043270764872431755
] |
[
0.9968337416648865,
0.002773622050881386,
0.00015605261432938278,
0.0002365889522479847
] |
en
| 0.999997 |
A random sample was recruited from children and adolescents ages 2–18 years who had been seen as inpatients or outpatients at Children's Hospital and Health Center between April 1 and June 30, 1998, and who were members of the health plan. This sample excluded children with a discharge status of expired, children whose payer was from the victim/witness fund, and children whose parents had requested their phone number and address to be kept private. Research assistants called parents of children on this list and obtained verbal informed consent. The research assistant verbally administered the PedsQL™ 4.0 to parents. This research protocol was approved by the institutional review board at Children's Hospital and Health Center, San Diego (#98-020).
|
15361252_p11
|
15361252
|
Procedure
| 2.444082 |
biomedical
|
Study
|
[
0.9884300231933594,
0.004202886484563351,
0.007367047946900129
] |
[
0.9953250885009766,
0.004296315833926201,
0.0001646280288696289,
0.000213971157791093
] |
en
| 0.999997 |
We pooled the data from the two samples. Previous reasearch on the PedsQL™ has documented the lack of mode of administration effects . In order to test the primary hypothesis that HRQL would prospectively predict healthcare costs, multiple linear regression analyses were conducted. We examined the association between age, gender, chronic health condition status (variables typically used by health plans to predict risk), and PedsQL™ 4.0 scores with healthcare costs at each of the three cumulative follow-up periods. We did not use socioeconomic status, as eligibility criteria for membership in the health plan requires families to have incomes below a certain level, and this restricts the range of this variable. Four models were constructed for each follow-up period. Model 1 included age and gender only, Model 2 included age, gender, and chronic health condition status, Model 3 included age, gender, and PedsQL™ 4.0 scores, and Model 4 included age, gender, chronic health condition status, and PedsQL™ 4.0 scores. We report the adjusted R 2 , a measure of the percent of variance in the dependent variable accounted for by the predictor variables while adjusting for the complexity of the model, and the standardized regression coefficient, or beta, for each predictor.
|
15361252_p12
|
15361252
|
Statistical analysis
| 4.119499 |
biomedical
|
Study
|
[
0.999037504196167,
0.00047526918933726847,
0.0004872723657172173
] |
[
0.9995287656784058,
0.00016697867249604315,
0.0002566961629781872,
0.00004764381446875632
] |
en
| 0.999997 |
PedsQL™ 4.0 scores were skewed toward the high end of the scale and were transformed by taking the square root of the reverse of the score (sqrt(100-score)) in order to create a more normal distribution. The distribution of cost data was skewed to the lower end, with many children having little cost and a relatively smaller number of children having high costs. These data were normalized by taking the log of the costs.
|
15361252_p13
|
15361252
|
Statistical analysis
| 3.602178 |
biomedical
|
Study
|
[
0.9981597065925598,
0.0004660692356992513,
0.001374195795506239
] |
[
0.9951017498970032,
0.0044579035602509975,
0.0003529721579980105,
0.00008730952686164528
] |
en
| 0.999997 |
In order to explore whether HRQL and chronic health condition status together would define a relatively small subset of enrollees who accounted for a disproportionately large percent of healthcare costs, we divided the sample into quintiles based on the PedsQL™ 4.0 Physical Functioning Scale score and into two groups based on chronic health condition status. Those children who fell in the lowest PedsQL™ 4.0 quintile and who reported the presence of a chronic health condition were assigned to the high-risk group. We describe the percent of costs, per member costs, and per member per month costs per child accounted for by this high risk group.
|
15361252_p14
|
15361252
|
Statistical analysis
| 3.800592 |
biomedical
|
Study
|
[
0.9977238774299622,
0.0008904564310796559,
0.0013855715515092015
] |
[
0.9992826581001282,
0.0005210551316849887,
0.00014080858090892434,
0.000055562570196343586
] |
en
| 0.999998 |
Data was collected from the parents of 317 children (157 girls, 160 boys) ages 2 to 18 years. The average age of the children was 8.3 years (SD = 4.14) with a range of 2.03 to 17.13 years. The sample was heterogeneous with respect to race/ethnicity, with 76 (25.4%) White non-Hispanic, 155 (51.8%) Hispanic, 39 (13.0%) Black non-Hispanic, 6 (2.0%) Asian/Pacific Islander, 3 (1.0%) American Indian or Alaskan Native, 20 (6.7%) Other, and 19 (6.0%) missing. With respect to mother's education, 36.4% had less than a high school education, 46.6% had a high school diploma or some college, and 7.0% were college graduates or beyond (18.8% missing). The measures were administered in two languages – English (n = 233, 73.6%) and Spanish (n = 84, 26.4%). The sample represented both chronically ill (n = 102, 32.1%) and healthy children (n = 215, 67.9%), based on parent report of the presence of a chronic health condition. Table 1 presents the chronic health conditions reported by parents for the high risk group and the non-high risk group.
|
15361252_p15
|
15361252
|
Descriptive Statistics
| 3.314816 |
biomedical
|
Study
|
[
0.9936169385910034,
0.0006951559917069972,
0.00568788917735219
] |
[
0.9995524287223816,
0.0003114319406449795,
0.00009022145968629047,
0.000045887303713243455
] |
en
| 0.999998 |
There were no differences found in PedsQL™ scores between the group sampled at well-child checks or specialty clinics and that sampled by phone.
|
15361252_p16
|
15361252
|
Descriptive Statistics
| 1.727702 |
biomedical
|
Study
|
[
0.9693798422813416,
0.012981239706277847,
0.017638884484767914
] |
[
0.9667001366615295,
0.030967608094215393,
0.0014248013030737638,
0.0009074307163245976
] |
en
| 0.999998 |
All 317 children were enrolled in the health plan after 6 months, with 314 (99.0%) enrolled after 12 months, and 244 (76.9%) after 24 months. There were no differences between those enrolled versus not enrolled at 24 months in percent with a chronic health condition, race/ethnicity, mother's education, or PedsQL™ scores. The cost per member per month (pmpm) for this sample, which represents the total cost divided by the number of members divided by the number of months enrolled, was $149 at 6 months, $137 at 12 months, and $115 at 24 months.
|
15361252_p17
|
15361252
|
Descriptive Statistics
| 2.478369 |
biomedical
|
Study
|
[
0.9274085760116577,
0.035275280475616455,
0.037316158413887024
] |
[
0.9789455533027649,
0.019981825724244118,
0.0004919670755043626,
0.0005806031404063106
] |
en
| 0.999998 |
The sample included 4,954 claims (there are multiple claims in a single clinical encounter) over the 24 months. The largest category of visits was for upper respiratory infections (URIs) and related infections (10.96%). Asthma, other infections, otitis media, and pain each account for 5 to 6% of visits, with acute orthopedic conditions accounting for 2.6% of visits. These most common diagnoses account for more than a third (38.7%) of the visits, the rest is comprised of a large number of relatively low-frequency diagnoses. This distribution of diagnoses is similar to the epidemiology of childhood illness, in that much of pediatric morbidity is accounted for by a large number of relatively low frequency diagnoses .
|
15361252_p18
|
15361252
|
Descriptive Statistics
| 3.958113 |
biomedical
|
Study
|
[
0.9977978467941284,
0.0016247828025370836,
0.0005774149321950972
] |
[
0.9986936450004578,
0.0009332006447948515,
0.00026168825570493937,
0.00011148936755489558
] |
en
| 0.999998 |
Table 2 displays the descriptive statistics for the PedsQL™ 4.0 parent proxy-report at Time 1. Consistent with previous PedsQL™ 4.0 findings, chronically ill children had lower HRQL scores than healthy children (Table 2 ).
|
15361252_p19
|
15361252
|
Descriptive Statistics
| 2.088608 |
biomedical
|
Study
|
[
0.9919216632843018,
0.0024333156179636717,
0.005645121913403273
] |
[
0.9956884980201721,
0.003639386035501957,
0.00045088911429047585,
0.00022113940212875605
] |
en
| 0.999997 |
Table 3 displays the results of the multiple regression analyses predicting healthcare costs for 6, 12, and 24 month follow-up. As can be seen, Model 1, with age and gender as the only predictors variables, did not account for significant variance in costs. Model 2 shows that age and gender, with chronic health condition status accounted for an increasing percentage of costs as the follow-up time lengthened. This pattern holds true as well for Model 3, which included age, gender, and the PedsQL™ 4.0 scores. Model 4, comprised of age, gender, chronic health condition status, and PedsQL™ 4.0 scores, accounted for the most variance, explaining 10.1% 14.4% and 21.2% of the variance in healthcare costs at 6, 12, and 24 month follow-up intervals. Inspection of the standardized regression coefficients for each predictor in Model 4 shows that, of the four predictors used, chronic health condition status and the PedsQL™ 4.0 Physical Functioning Scale scores consistently accounted for the greatest amount of variance.
|
15361252_p20
|
15361252
|
Multiple regression analysis
| 4.139392 |
biomedical
|
Study
|
[
0.9980663657188416,
0.000937746255658567,
0.0009958642767742276
] |
[
0.9994370341300964,
0.0001796224678400904,
0.00032591968192718923,
0.00005735316517530009
] |
en
| 0.999998 |
We used the two variables accounting for most of the variance in the regression analysis – the PedsQL™ 4.0 Physical Functioning scores and chronic health condition status – to describe the percentage of costs accounted for by different groups of children. In order to create a single denominator for the percentages, we used the 241 children continuously enrolled in the health plan with complete data for this set of analyses. To create quintiles, we determined the values that divided the sample into five equal-sized groups based on PedsQL™ 4.0 Physical Functioning Scale scores. Enrollees with a score of less than 75 on the PedsQL™ 4.0's 0–100 scale were in the first quintile (N = 51; 21.0%). The second quintile (N = 45; 18.5%) was bounded by the scores 75.0 to 90.624, the third quintile (N = 48; 19.6%) by the scores 90.625 to 96.874, the fourth quintile by the scores 96.875 to 100 (N = 18; 7.3%), and the fifth quintile consisted of enrollees scoring 100 (N = 81; 33.4%). Because the distribution of these PedsQL™ 4.0 scores was skewed, we combined the fourth and fifth quintiles (N = 99; 40.7%; 2 missing).
|
15361252_p21
|
15361252
|
Defining the high risk group
| 4.045375 |
biomedical
|
Study
|
[
0.9985352754592896,
0.0007166005088947713,
0.0007480798522010446
] |
[
0.9994968175888062,
0.00031493345159105957,
0.00013864191714674234,
0.00004950331640429795
] |
en
| 0.999997 |
Table 4 shows the percentage of total costs accounted for by children across PedsQL™ 4.0 Physical Functioning Scale quintiles and chronic health condition status, for the three cumulative follow up periods. As can be seen, children in the high risk group (the subset of chronically ill children in the lowest quintile), account for a disproportionately large share of healthcare costs. This group, comprising just 8.7% of the sample, accounted for 37.42% of the healthcare costs over six months, 59.16 % of costs over 12 months, and 61.74% of costs over 24 months.
|
15361252_p22
|
15361252
|
Defining the high risk group
| 3.838429 |
biomedical
|
Study
|
[
0.9957492351531982,
0.0017018519574776292,
0.002548856195062399
] |
[
0.9992555975914001,
0.0004642449493985623,
0.0002233031264040619,
0.0000568405375815928
] |
en
| 0.999998 |
Table 5 shows the total costs, the per member costs, and the per member per month (pmpm) costs for the high risk group and the not high risk group over the three follow-up periods. As can be seen, the high risk group was an extremely costly subset of enrollees for each of the cumulative 6 month periods, as measured by total, per member, or pmpm costs. Pmpm costs were quite disparate between the high risk group and other enrollees. For the high risk group at 6 months, pmpm was $432 (vs. $66 for the other patients), at 12 months pmpm was $809 (vs. $61), and at 24 months, pmpm was $722 (vs. $60).
|
15361252_p23
|
15361252
|
Defining the high risk group
| 2.799673 |
biomedical
|
Study
|
[
0.8698973655700684,
0.007789614610373974,
0.12231305986642838
] |
[
0.9928343296051025,
0.006732456386089325,
0.00026733559207059443,
0.0001658109831623733
] |
en
| 0.999996 |
This study tested the primary hypothesis that HRQL could prospectively predict healthcare cost in pediatric patients in a managed care environment. We measured age, chronic health condition status, and PedsQL™ 4.0 scores at Time 1, and prospectively measured utilization, via costs based on claims and encounter data, for three cumulative periods. These data demonstrate that parent-reported HRQL, as measured by the PedsQL™ 4.0, and chronic health condition status each accounted for significant variance in healthcare costs over 6, 12, and 24 months. The data further show how these two predictor variables, chronic health condition status, and PedsQL™ 4.0 Physical Functioning scores, define a relatively small group of enrollees that accounted for a large percentage of total healthcare costs.
|
15361252_p24
|
15361252
|
Discussion
| 4.136351 |
biomedical
|
Study
|
[
0.998350977897644,
0.0011566166067495942,
0.0004924791865050793
] |
[
0.9993483424186707,
0.00027171889087185264,
0.00028933375142514706,
0.00009061430318979546
] |
en
| 0.999997 |
This high risk group displays disproportionately high costs as early as 6 months, and their pmpm costs peak at one year. This suggests the importance of managing high risk enrollees as soon as they are identified, perhaps as early as their initial enrollment. It also implies the potential for significant return on investment for better case management, even in the first six months of enrollment. The high risk group's costs remain disproportionately high throughout the 24 months of the study. This fact suggests that the method used here for identifying the high risk group succeeded in identifying children with high ongoing care needs and costs, as opposed to children with one-time health care needs. An anomalous finding was that children in the third quintile on PedsQL™ scores who had chronic health conditions were, for an unexplained reason, much less costly than their peers.
|
15361252_p25
|
15361252
|
Discussion
| 3.496636 |
biomedical
|
Study
|
[
0.9795684814453125,
0.0030658829491585493,
0.01736569218337536
] |
[
0.9969033598899841,
0.00267775054089725,
0.0003029658109880984,
0.0001158995000878349
] |
en
| 0.999998 |
It is worth comparing the mean PedsQL™ 4.0 scores for the high risk group to other published data. The high risk group had scores of 44.5 for the Physical Functioning Scale, 70.7 for the Psychosocial Summary Scale, and 61 for the Total Scale. This is placed in clinical perspective by other data showing that scores for children with cancer, in active treatment, are 65, 68, and 67 for the Physical, Psychosocial and Total scales, respectively. .
|
15361252_p26
|
15361252
|
Discussion
| 3.67838 |
biomedical
|
Study
|
[
0.99764484167099,
0.0017276644939556718,
0.0006274853367358446
] |
[
0.9952958226203918,
0.0033864248543977737,
0.001120275934226811,
0.0001975229533854872
] |
en
| 0.999997 |
A hypothetical example is presented to illustrate the potential impact of these findings. In a typical health plan, the rate of chronic health conditions will most likely be between 5% and 18% , rather than the 31.4% rate we found by selecting our sample, in part, from hospital specialty clinics. We will further conservatively assume that one-fifth (20%) of children with chronic health conditions would fall in the lowest quintile on the PedsQL™ 4.0. If this were so, then between 1% (5% chronic health condition × 20% in the lowest quintile) and 3.6% (18% chronic health condition × 20% in the lowest quintile) of enrollees in a health plan would fall into the high risk group. Thus, in a hypothetical medium to large health plan with 50,000 pediatric enrollees, the high risk group would be comprised of anywhere from 500 (1% of 50,000) to 1800 (3.6% of 50,000) children. Using the costs figures from this sample ($722 pmpm), this hypothetical high risk group represents between $8.6 and $31.2 million in costs over the course of 24 months. This example relies on speculation and is intended as a hypothetical case, for illustrative purposes only.
|
15361252_p27
|
15361252
|
Discussion
| 3.863656 |
biomedical
|
Study
|
[
0.9944024682044983,
0.00237533962354064,
0.0032221742440015078
] |
[
0.974075436592102,
0.024397917091846466,
0.0011582471197471023,
0.0003683200047817081
] |
en
| 0.999997 |
Taken together, these findings represent an alternative method toward the prospective prediction of healthcare costs in pediatric federally supported managed care populations. While a percentage of these identified costs are inevitable, due to the costs of appropriate care for these chronically ill, poorly functioning children, the possibility exist that a proportion of these healthcare costs are avoidable. Evidence-based disease management has been shown to reduce healthcare costs and increase HRQL in certain chronic conditions such as asthma . By identifying at-risk children with low PedsQL™ 4.0 scores, targeted interventions may avert certain future healthcare costs by ameliorating impaired HRQL when first identified.
|
15361252_p28
|
15361252
|
Discussion
| 4.009377 |
biomedical
|
Study
|
[
0.9986099004745483,
0.0007362121832557023,
0.000653896713629365
] |
[
0.9939749836921692,
0.002093710470944643,
0.0038232714869081974,
0.00010807454964378849
] |
en
| 0.999998 |
Certain limitations exist in this study. The first has to do with data not accounted for in this study. We did not have access to pharmacy and mental health costs, nor did we have access to out-of-plan expenditures. For mental health costs, however, recent data has shown that children referred for psychiatric services demonstrate child self-report and parent proxy-report PedsQL™ 4.0 Total Scale Scores comparable to children with chronic physical health conditions . Those data suggest that this methodology may be useful in predicting mental health costs as well. We did not include children under the age of two. Neonatal intensive care, for example, is a large percent of the costs for Medicaid managed care plans . The portion of health plan costs devoted to caring for children under two is not explored here. However, many of these costs cannot be avoided, and preventive efforts for these costs are most appropriately targeted at the prenatal and perinatal periods. Finally, we did not compare the performance of these variables to that of existing administrative risk adjustment methods currently available.
|
15361252_p29
|
15361252
|
Discussion
| 3.086534 |
biomedical
|
Study
|
[
0.9820871353149414,
0.0015267664566636086,
0.016386093571782112
] |
[
0.9976702332496643,
0.0019128302810713649,
0.0003074078122153878,
0.00010943697270704433
] |
en
| 0.999997 |
The second limitation has to do with sampling issues and with generalizing these data beyond this study. Our data was not collected at enrollment, nor did we sample from the entire pool of enrollees. Further research is necessary to determine whether these findings hold true for children assessed at health plan enrollment, and to determine the extent to which the results may be influenced by the convenience sample used here. The sample was too small to use cross-validation techniques. Prediction models tend to overfit the development sample, and the predictive validity of these variables should be tested in other, larger samples. Although generalization of these findings to broader populations should be made with caution, the sample here is very diverse with respect to race/ethnicity, and thus likely to be similar to other federally support health plans. We also combined data from two different samples – specialty clinic patients, and health plan members who had been seen in the hospital or outpatient clinics at least three months after the clinical encounter. These two groups could have had unmeasured systematic differences, which could have biased the results.
|
15361252_p30
|
15361252
|
Discussion
| 3.861606 |
biomedical
|
Study
|
[
0.9970234036445618,
0.0007495975005440414,
0.0022269212640821934
] |
[
0.999275267124176,
0.0004734336689580232,
0.00020379516354296356,
0.00004745038313558325
] |
en
| 0.999996 |
The third has to do with using a survey to gather these data. The costs of fielding a survey can be quite high, and, if tied to payment, survey responses are subject to "gaming". However, we submit that the potential gains from optimal management of an enrolled population will almost certainly be greater than the costs of survey administration. Moreover, while gaming might occur if health plans were to be compensated based on the HRQL of their enrolled population, the methods used here are suggested as strategies for clinical management, not for rate setting, thus reducing the incentives for gaming. We did not track refusal rates and so do not know what percent of potential participants consented to be in the study. Finally, using a survey means that parents reported on their children's chronic health condition information. Objective measures of chronic health condition would strengthen the validation process. However, in previous PedsQL™ 4.0 clinical research in pediatric patients with cancer, cardiac and rheumatic chronic health conditions, objective medical diagnosis of these chronic diseases demonstrated similar differences between healthy children and children with chronic health conditions as shown in the present findings .
|
15361252_p31
|
15361252
|
Discussion
| 3.907158 |
biomedical
|
Study
|
[
0.9987275004386902,
0.00046083415509201586,
0.0008115973323583603
] |
[
0.9990204572677612,
0.0006055766134522855,
0.00031494160066358745,
0.00005894293644814752
] |
en
| 0.999998 |
Further research is necessary. First, a much larger, and randomly selected sample is necessary to confirm these results. Second, split-half validation should be performed so that the coefficients from one group are used to predict the costs in a different group. This could be done with split halves of one large group, or with two similar groups enrolled at different points in time. Given that our regression equation explains 21% of costs, further studies could be done to determine whether other variables might account for additional variance in costs. Further studies could also allow comparison and validation with the results here.
|
15361252_p32
|
15361252
|
Discussion
| 3.233775 |
biomedical
|
Study
|
[
0.9830104112625122,
0.0004665630985982716,
0.016523007303476334
] |
[
0.9679843783378601,
0.030825581401586533,
0.0010528629645705223,
0.00013717557885684073
] |
en
| 0.999998 |
This is the first study we are aware of to use parent reports of pediatric HRQL and chronic health condition status to prospectively predict healthcare costs in a pediatric sample. These data have implications for healthcare decision makers such as pediatricians, health plan administrators, and policymakers. In a prospective payment system, providers are incentivized to actively manage high-risk patients and to provide care at the appropriate level. The idea behind such a system is that prevention and appropriate care accrues benefits to patients in the form of better health and to providers in the form of lower costs. If, as these data suggest, parent reports of HRQL can be used to predict healthcare costs, one could identify at-risk children proactively and intervene to avoid both illness and costs. In this way, these data can serve simultaneously to improve the health of children and the system that serves them.
|
15361252_p33
|
15361252
|
Conclusion
| 4.056807 |
biomedical
|
Study
|
[
0.9985617995262146,
0.0007163431728258729,
0.0007218423415906727
] |
[
0.9989027976989746,
0.0007087608682923019,
0.00032381241908296943,
0.00006463328463723883
] |
en
| 0.999997 |
HRQL Health-related Quality of Life
|
15361252_p34
|
15361252
|
List of Abbreviations
| 1.90196 |
biomedical
|
Other
|
[
0.8982086777687073,
0.014932366088032722,
0.08685900270938873
] |
[
0.011128585785627365,
0.9864323735237122,
0.0018246396211907268,
0.0006144247599877417
] |
en
| 0.999995 |
PedsQL™ 4.0 Pediatric Quality of Life Inventory™, Version 4.0
|
15361252_p35
|
15361252
|
List of Abbreviations
| 1.556263 |
biomedical
|
Other
|
[
0.9481082558631897,
0.006917706690728664,
0.04497404396533966
] |
[
0.00542561337351799,
0.9936515092849731,
0.0005219261511228979,
0.00040098302997648716
] |
en
| 0.999997 |
SD Standard Deviation
|
15361252_p36
|
15361252
|
List of Abbreviations
| 1.606238 |
biomedical
|
Other
|
[
0.8940222263336182,
0.002574329497292638,
0.10340339690446854
] |
[
0.12570509314537048,
0.8708495497703552,
0.002099035307765007,
0.0013463178183883429
] |
en
| 0.999993 |
CCS California Children's Services
|
15361252_p37
|
15361252
|
List of Abbreviations
| 1.045935 |
other
|
Other
|
[
0.01999444141983986,
0.002810896374285221,
0.977194607257843
] |
[
0.0017212547827512026,
0.9973394274711609,
0.00048412970500066876,
0.0004552449390757829
] |
en
| 0.999996 |
URI Upper respiratory infection
|
15361252_p38
|
15361252
|
List of Abbreviations
| 1.857002 |
biomedical
|
Other
|
[
0.9764243364334106,
0.011694948188960552,
0.011880675330758095
] |
[
0.007672032807022333,
0.9894731640815735,
0.0009551601251587272,
0.001899682218208909
] |
en
| 0.999995 |
PMPM per member per month
|
15361252_p39
|
15361252
|
List of Abbreviations
| 1.179674 |
other
|
Other
|
[
0.12488967925310135,
0.005149634554982185,
0.8699607849121094
] |
[
0.007093265186995268,
0.9911750555038452,
0.0009554835269227624,
0.0007761609740555286
] |
id
| 0.571429 |
MS, PSK, and JWV conceived of the research. MS and JWV supervised the data collection. MS and DS performed the data analysis. MS drafted the manuscript. JWV, PSK, and DS provided substantive input into the manuscript. All authors read and approved the final manuscript.
|
15361252_p40
|
15361252
|
Authors' Contributions
| 0.963361 |
other
|
Other
|
[
0.03070330061018467,
0.001361035625450313,
0.9679356813430786
] |
[
0.00232419790700078,
0.996791660785675,
0.0005138300475664437,
0.00037027389043942094
] |
en
| 0.999994 |
Watermelons and tomatoes are good sources of the carotenoid lycopene . However, bioavailability of lycopene is not directly related to plant content, and depends in a large part upon plant matrix effects. In tomatoes, heat processing and homogenization breaks protein-carotenoid complexes, releases lycopene from cell wall linkages and improves human uptake of this compound , while heat processing is not necessary for adequate uptake of lycopene from watermelon juice . Extracts of both foods exhibit antioxidant activity in vitro and function is attributed to lycopene since isolated lycopene demonstrates strong oxygen and peroxy radical scavenging properties .
|
15369594_p0
|
15369594
|
Background
| 4.130677 |
biomedical
|
Study
|
[
0.9995480179786682,
0.00012466925545595586,
0.00032732560066506267
] |
[
0.9873535633087158,
0.0027176353614777327,
0.009799201972782612,
0.00012951140524819493
] |
en
| 0.999997 |
Recent epidemiological studies have linked reductions in risks of cardiovascular disease with diets rich in lycopene containing foods. These reductions in risk have been primarily attributed to the antioxidant properties of lycopene . Improved antioxidant parameters of lymphocytes have been reported in clinical trials that supplemented diets with 16.5 mg and 40 mg /day of lycopene from tomato puree and tomato juice, respectively . Other clinical trials have shown reductions in low-density lipoprotein (LDL) oxidation resulting from lycopene supplementation . LDL contains unsaturated fatty acids and can be oxidized by free radicals and peroxidizing agents. Since lycopene is primarily attached to LDL in plasma, it may protect against atherosclerosis through inhibition of lipid peroxidation and foam cell production .
|
15369594_p1
|
15369594
|
Background
| 4.130013 |
biomedical
|
Study
|
[
0.9992853999137878,
0.00048074641381390393,
0.00023381471692118794
] |
[
0.7553033232688904,
0.0019151627784594893,
0.24220949411392212,
0.000572005461435765
] |
en
| 0.999995 |
Other studies have assessed response of plasma lipids to lycopene-rich diets. In one study, six healthy men were supplemented with 60 mg/day for three months with tomato lycopene (LycoRed) with a 14% reduction in LDL-C and no change in HDL-C . Researchers concluded that lycopene was involved in controlling cholesterol synthesis and found the same results in a macrophage cell study . It is not known if other lycopene containing foods can act ex vivo as antioxidants or alter cholesterol levels.
|
15369594_p2
|
15369594
|
Background
| 3.920961 |
biomedical
|
Study
|
[
0.9997027516365051,
0.00013068657426629215,
0.00016650233010295779
] |
[
0.9951589703559875,
0.0007088748971000314,
0.004027037415653467,
0.00010507103434065357
] |
en
| 0.999996 |
The objectives of this study were to compare the ability of two lycopene containing foods, tomato and watermelon to provide cardiovascular protection to middle-aged adults by measuring changes in cholesterol levels and antioxidant ex vivo biomarkers.
|
15369594_p3
|
15369594
|
Background
| 4.030265 |
biomedical
|
Study
|
[
0.9993299245834351,
0.0004202515119686723,
0.00024977276916615665
] |
[
0.9991102814674377,
0.000458316586446017,
0.0003537797892931849,
0.00007760105654597282
] |
en
| 0.999998 |
Samples for this study came from a larger study, which has been reported in detail . This study was a diet-controlled, repeated measures crossover design with ten healthy non-smoking subjects, five men (average age 49 years) and five women (average age 51 years) recruited from the Beltsville, MD area (Table 1 ). In addition to a base diet, which provided 34% of energy from fat and minimal amounts of lycopene, subjects were randomly assigned to receive three dietary treatments for 3 weeks each: 1) control (no added lycopene); 2) 20.1 mg lycopene per day from watermelon juice; and 3) 18.4 mg lycopene per day from tomato juice. All subjects followed a low-lycopene diet for two weeks before the first treatment and during the four-week washout periods between treatments. Total study duration was 19 weeks. During treatment periods, all meals were prepared and consumed Monday through Friday at the Beltsville Human Nutrition Research Center's Human Studies Facility, and weekend meals were packed for off-site consumption. Blood was drawn from fasted subjects before treatment (the day before the start of study and on the first day of the study), prior to treatment and weekly during treatment. Plasma was separated from whole blood by centrifugation and stored at -80°C until analyzed for cholesterol and antioxidant activity.
|
15369594_p4
|
15369594
|
Experimental Design
| 4.146661 |
biomedical
|
Study
|
[
0.9984927177429199,
0.001250087982043624,
0.00025719619588926435
] |
[
0.9987465143203735,
0.0008449956076219678,
0.00026681716553866863,
0.0001416136510670185
] |
en
| 0.999996 |
Watermelon juice for the study was prepared at a pilot plant at the USDA Citrus and Subtropical Products Laboratory, Winter Haven, FL without heat treatment as previously described . Canned commercial tomato juice (Campbell's, Camden, NJ) was used for the tomato intervention. Juices were analyzed for carotenoid content using established extraction procedures with reversed phase HPLC with photo diode array detector (Waters Corp, Franklin, MA) . For watermelon treatment, subjects were given one bottle of juice (260 g each) at breakfast, lunch and dinner, which provided daily totals of 20.1 mg lycopene, 0.90 mg phytoene, 0.45 mg phytofluene and 2.5 mg beta carotene. The juice contained 94% trans lycopene and 6% cis isomers, primarily 5- cis and 13- cis with minimal amounts of other cis isomers . For tomato juice treatment, subjects were given one serving (122 g each) at breakfast and dinner, which provided daily totals of 18.4 mg lycopene, 2.1 mg phytoene, 1.1 mg phytofluene and 0.6 mg beta carotene with 89% of the lycopene as trans lycopene and 10.8% cis isomers, primarily identified as 5- cis , 9- cis , 13- cis , and 15- cis , and minimal amounts of other cis isomers .
|
15369594_p5
|
15369594
|
Juice Treatments
| 4.128828 |
biomedical
|
Study
|
[
0.9992475509643555,
0.00030190087272785604,
0.00045058922842144966
] |
[
0.9992215633392334,
0.0005447778385132551,
0.00018517536227591336,
0.0000484434021927882
] |
en
| 0.999995 |
Subsets and Splits
SQL Console for rntc/test-pp-aa
The query retrieves a sample of documents that are clinical cases with an educational score above 3, providing limited analytical value.
Clinical Cases Sample
Returns a sample of 100 clinical case documents, providing a basic overview of the document type's content.